Nitric oxide releasing steroids

ABSTRACT

The invention relates to nitrooxyderivative of corticosteroids of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof 
       R—(Z) a —R x   (I)
 
     wherein R is the corticosteroid residue of formula (II): 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1  is OH, R 2  —CH 3 , or R 1  and R 2  are taken together to form a group of formula (III)
 
     
       
         
         
             
             
         
       
         
         
           
             R 3  is Cl or F; 
             R 4  is H or F;
 
wherein R 1 , R 2 , R 3  and R 4  can be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
 
with the proviso that:
 
when R 1  and R 2  are the group of formula (III) then R 3  is F and R 4  is H or F;
 
           
         
       
    
     The compounds are useful in the treatment of respiratory diseases, inflammatory diseases, dermatological diseases and ocular diseases.

FIELD OF THE INVENTION

The present invention relates to steroidal compounds having an improvedpharmacological activity and lower side effects, to a process for theirpreparation and to pharmaceutical formulation containing them.

The compounds of the present invention may be used, as drugs havingantiinflammatory activity at peripheral level, for the therapy ofrespiratory diseases such as asthma and COPD, in ocular diseasetherapies such as ocular hypertension, age-related macular degeneration,diabetic macular edema, diabetic retinopathy, hypertensive retinopathyand retinal vasculopathies, or in dermatological disease therapies suchasdermatosis, atopic dermatitis, inflammation, eczema, erythema,papulation, scaling, erosion, oozing, crusting, pruritis, psoriasis,epidermalysis bullosa, erythema, hidradenitis suppurative, warts, diaperrash, jock itch. In particular the compounds of the present inventionare useful in ocular disease therapies.

BACKGROUND OF THE INVENTION

In the prior art nitrooxy derivatives of steroids, which are usable alsoas cardiovascular agents for the coronary insufficiency or anginapectoris therapy, are described.

For example, German patent DE 2,222,491 describes the preparation ofpregnane derivatives having in position 21 the —CH₂—O—NO₂ group. In saidpatent it is stated that said derivatives have a cardiotropic activity.This activity represents a drawback for said compounds, since theymodify the cardiac frequency.

U.S. Pat. No. 3,494,941 describes steroid derivatives from3-hydroxy-extrane or from extr-4 en-3 one, used as vasodilators in thetreatment of cardiac affections such as coronary insufficiency andangina pectoris. In the structure of said compounds a —ONO₂ group is atthe free end of the alkylene chain which is linked by an ether bond tothe steroid in position 17. According to said patent it is possible tohave nitrate groups also in the positions 3 and 16 of the steroidalstructure. The same drawbacks mentioned above as regards the effects onthe cardiac frequency can be repeated for the compounds of this patent.

U.S. Pat. No. 3,183,252 describes derivatives of16-nitrate-alkylpre-gnanes wherein the alkyl group is linked to thepregnane structure by a carbon-carbon bond. The compounds according tosaid patent can be used as vasodilators. The same drawbacks reported forthe above prior art can be repeated.

WO 98/15568 and WO 03/064443 in the name of the Applicant describenitrate esters of steroidal compounds, wherein between the steroidalstructure and the nitrooxy group a bivalent linking group is inserted.Said compounds show a good efficacy and/or good tolerability withrespect to the corresponding precursors.

Patent application WO 00/61604 in the name of the Applicant describesnitrooxy derivatives of steroidal compounds with various linking groupshaving at one end a nitrooxy group, and covalently linked with the otherend to a steroidal compound. In said application the uses concern thecompounds usable in the treatment of patients in oxidative stress. Saidcompounds contain in the molecule also a bivalent linking group whichmust be capable to prevent the free radicals production and is selectedon the basis of the tests reported therein.

SUMMARY OF THE INVENTION

The Applicant has surprisingly and unexpectedly found a class of nitricoxide releasing compounds with a better bioavailability and/or aprolonged release of NO in comparison with the compounds known in priorart. In general the compounds of the present invention have a betterdrugability in comparison to the corresponding compounds of the priorart.

DETAILED DESCRIPTION OF THE INVENTION

Object of the present invention are compounds of general formula (I) andpharmaceutically acceptable salts or stereoisomers thereof

R—(Z)_(a)—R_(x)  (I)

wherein R is a corticosteroid residue of formula (II):

wherein:R₁ is OH, R₂ —CH₃, or R₁ and R₂ are taken together to form a group offormula (III)

R₃ is Cl or F;

R₄ is H or F;

wherein R₁, R₂, R₃ and R₄ can be linked to the correspondent carbonatoms of the steroidal structure in position α or β;with the proviso that:when R₁ and R₂ are the group of formula (III) then R₃ is F and R₄ is Hor F;when R₁ is OH and R₂ —CH₃ then R₄ is H and R₃ is Cl or F;preferred corticosteroid radicals are R of formula (II) wherein:R₁ is OH in position α, R₂ —CH₃ in position β, R₃ is Cl in position αand R₄ is H; orR₁ is OH in position α, R₂ —CH₃ in position β, R₃ is F in position α andR₄ is H; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ is F and R₄ is H, R₁, R₂ and R₃ are in position α; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ and R₄ are F, R₁, R₂, R₃ and R₄ are in position α;a in formula (I) is equal to 0 or 1;Z is a group capable of binding R_(x) and is selected from —C(O)—, or—CH(R′)—O— wherein R′ is selected from H or a straight or branched C₁-C₄alkyl, preferably R′ is H or —CH₃;R_(x) is a radical and is selected from the the following meanings:

A)

—HN—CH(R¹)—C(O)-(T-Y—ONO₂)  (a1)

—C(O)—CH(R¹)—NH-(T′-Y—ONO₂)  (a2)

—HN—CH(R^(1a)-T″-Y′—ONO₂)—COOR^(3a)  (a3)

—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NHR^(4a)  (a4)

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂)  (a5)

—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)

—HN—CH(R^(1a)-T″-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a7)

—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a8)

—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9)

—R^(1b)—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a10)

wherein:

R¹ is selected from:

A1) H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl,methylthio-(CH₂)₂—, phenyl, benzyl, C₆H₅—CH₂—CH₂-, 2-monosubstitutedbenzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl whereinthe substituent of the benzyl is selected from —F, —Cl, —I, —NO₂, —CF₃,—CH₃, CN, C₆H₅CO—;

2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl,2-pyrrolidyl, 3-triptophanyl-CH₂—, 3-benzothienyl-CH₂—,4-imidazolyl-CH₂—, 9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—,cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-B(OH)₂-benzyl,4-quinolyl-CH₂—, 3-quinolyl-CH₂—, 2-quinolyl-CH₂—, 2-quinoxalyl-CH₂—,2-furyl-CH₂—, 1-naphtyl-CH₂—, 2-naphtyl-CH₂—, 2-pyridyl-CH₂-,3-Pyridyl-CH₂-, 4-pyridyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—,C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—, CH═CH—CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,NH₂(═NH)NH—(CH₂)₃—, P(═O) (OCH₃)₂, I—CH₂—, preferably R¹ is H, —CH₃,isopropyl, benzyl;

A2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)],—CH₂-[(C₆H₂)-(3,5-diiodo)-(4-OH)], —CH₂-[(C₆H₃)-(3-nitro)-(4-0H)],preferably R¹ is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];

A3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ isH, —C(O)CH₃ or

wherein R^(5a) is H or a linear or branched C₁-C₁₃ alkyl chain,preferably R^(5a) is H or a linear (C₁-C₅) alkyl, preferably R¹ is—(CH₂)₄—NHR″, wherein R″ is as above defined;

A4) —CH—C(O)R″′, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is—OR^(5a) or

wherein R^(5a) is as above defined, preferably R¹ is —CH₂—C(O)R′″,wherein R′″ is as above defined;R^(1a) is selected from,

A5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—, —CH₂[(C₆H₄)-(4-O)—],—CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—],preferably R^(1a) is —CH₂—O—;

A6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^(1a)is —(CH₂)₄—NH— or —CH₂—NH—;

A7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^(1a) is—CH₂—C(O)—;

R^(3a) is selected from H, —R^(5a) or

wherein R^(5a) is as above defined;

R^(4a) is selected from H or —C(O)CH₃ or

wherein R^(5a) is as above defined;

R^(1b) is selected from

A8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—,[-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]-CH₂—,preferably R^(1b) is —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;

A9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄— preferably R^(1b) is—HN—(CH₂)₄— or —HN—CH₂—;

A10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^(1b) is—C(O)—CH₂—;

T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is —C(O)—NR′—wherein R′ is as above defined;T″ is independently selected from —C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—,—S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O—, wherein X″ and R′ areas above defined, with the proviso that T″ is —C(O)—C(O), —C(O)—X″— or—C(O)—NR′— when T″ is linked to —NH—, —O—, or —S—; orT″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O— C(O)O-when T″ islinked to —C(O)—;Y and Y′ are as below defined;

B)

—HN—CH(R²)—CH₂C(O)-(T-Y—ONO₂)  (b1)

—C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)  (b2)

—HN—CH(R^(2a)-T″-Y′—ONO₂)—CH₂COOR^(3a)  (b3)

—C(O)—CH₂—CH(R^(2a)-T″-Y′—ONO₂)—NHR^(4a)  (b4)

—R^(2b)—CH(NHR^(4a))—CH₂C(O)-(T-Y—ONO₂)  (b5)

—R^(2b)—CH(CH₂COOR^(3a))NH-(T′-Y—ONO₂)  (b6)

—HN—CH(R^(2a)-T″-Y′—ONO₂)—CH₂—C(O)-(T-Y—ONO₂)  (b7)

—C(O)—CH₂—CH(R^(2a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (b8)

—R^(2b)—CH(NH-T′-Y′—ONO₂)—CH₂C(O)-(T-Y—ONO₂)  (b9)

—R^(2b)—CH(CH₂C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (b10)

wherein

R² is selected from

B1) H, —CH₃, CF₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—,phenyl, benzyl, 3-triptophanyl-CH₂—, NH₂—C(O)—CH₂—, NH₂—C(O)—(CH₂)₂—,NH₂ (═NH) NH—(CH₂)₃—, tBuO—CH(CH₃)—, benzyl-O—CH₂—, 4-terbutoxy-benzyl,4-phenylbenzyl, preferably R² is H, —CH₃, isopropyl, benzyl;

B2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)],—CH₂—[(C₆H₂)-(3,5-diiodo)-(4-OH)], —CH₂-[(C₆H₃)-(3-nitro)-(4-OH)];

B3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R′″ isas above defined, preferably R² is —(CH₂)₄—NHR

B4) —CH—C(O)—R′″, —(CH₂)₂—C(O)—R′″, —(CH₂)₄—C(O)—R′″ wherein R′″ is asabove defined, preferably R² is —CH—C(O)—R′″;

R^(2a) is selected from

B5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—],—CH₂-[(3,5-diiodo)-(C₆H₂)—(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—],preferably R^(2a) is —CH₂—O—;

B6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^(2a)is (CH₂)₄—NH— or —CH₂—NH—;

B7) —CH—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^(2a) is—CH₂—C(O)—;

R^(2b) is selected from

B8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—,[-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—,preferably R^(2b) is —O—CH₂— or [-(4-O)—(C₆H₄)]-CH₂—;

B9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^(2b)is —HN—(CH₂)₄— or —HN—CH₂—;

B10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄, preferably R^(2b) is—C(O)—CH₂—;

R^(3a) and R^(4a) are as above defined;T, T′ and T″ are as above defined and Y and Y′ are as below defined;

C)

—HN—(CH₂)_(b)—C(O)-(T-Y—ONO₂);  (c1)

—C(O)—(CH₂)_(b)—NH-(T′-Y—ONO₂);  (c2)

wherein b is an integer from 3 to 6,T and T′ are as above defined and Y and Y′ are as below defined; D)

—HN—CH(R¹²)—CH₂—O-(T″-Y—ONO₂)  (d1)

—O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)  (d2)

—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂OH  (d3)

—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NHR^(4a)  (d4)

—R^(12b)—CH(NHR^(4a))—CH₂—O-(T″-Y—ONO₂)  (d5)

—R^(12b)—CH(CH₂OH)—NH-(T′-Y—ONO₂)  (d6)

—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂—O-(T″-Y—ONO₂)  (d7)

—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d8)

—R^(12b)—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T″-Y—ONO₂)  (d9)

—R^(12b)—CH(CH₂—O-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d10)

whereinT′″ is independently selected from —C(O)—, —C(O)X″— wherein X″ is —O— or—S—, or —C(O)—NR′— wherein R′ is as above defined;T′ and T″ are as above defined;Y and Y′ are as below defined;R¹² is selected from:

D1) H, —CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, NH₂(═NH) NH—(CH₂)₃, preferably R¹² is H;

D2) —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)],—CH₂-[(C₆H₃)-(3,5-diiodo)-(4-OH)], —CH₂—[(C₆H₃)-(3-nitro)-(4-OH)],preferably R¹² is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];

D3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ isas above defined, preferably R¹² is —(CH₂)₄—NHR″;

D4) —CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is asabove defined, preferably R¹² is —CH₂—C(O)R″;

R^(12a) is selected from

D5) —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—],—CH₂-[3,5-diiodo-(C₆H₂)-(4-O)—], —CH₂-[3-nitro-(C₆H₃)-4-O—], preferablyR^(12a) is CH₂—O— or —CH₂[(C₆H₄)-(4-O)—];

D6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^(12a)is —(CH₂)₄—NH— or —CH₂—NH—;

D7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^(12a) is—CH₂—C(O)—;

R^(12b) is selected from

D8) —O—CH₂—, —O—CH(CH₃)—, [-(4-O)—(C₆H₄)]—CH₂—,[-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—,preferably R^(12b) is —O—CH₂— or [-(4-O)—(C₆H₄)]-CH₂—;

D9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₂—, —HN—(CH₂)₄—, preferably R^(12b)is —HN—(CH₂)₄— or —HN—CH₂—;

D10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^(12b) is—C(O)—CH₂—;

R^(4a) is as above defined;

wherein c is equal to 0 or 1, d is an integer from 0 to 3 with theproviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3, Tand T′ are as above defined and Y is as below defined;

wherein e and f are equal to 0 or 1, with the proviso that f is 0 when eis 0 and f is 0 or 1 when e is 1,T and T′ are as above defined and Y is as below reported;

wherein R³ is H, CH₃, propyl, (C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl, allyl,2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl,4-bromobenzyl, 4-methylbenzyl, preferably R³ is H,T and T′ are as above defined and Y is as below defined;

wherein R⁴ is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are asabove defined and Y is as below defined;

wherein R⁵ is H, R⁶ is H, or R⁵ and R⁶ when taken together are a doublebond, T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein c is as above defined, d is equal to 0 or 1, T and T′ are asabove defined and Y is as below reported;

wherein R⁷ is H, R⁸ is H, or R⁷ and R⁸ when taken together are a doublebond, c is as above defined, T and T′ are as above defined and Y is asbelow reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein R⁹ and R¹⁰ are H, CH₃, R¹¹ is CH₃ or 4-piperidinyl with theproviso that R⁹ and R¹⁰ are H when R¹¹ is 4-piperidinyl and R⁹ and R¹⁰are CH₃ when R¹¹ is CH₃, T and T′ are as above defined and Y is as belowreported;

wherein T and T′ are as above defined and Y is as below reported;with the proviso that in the formula (I):a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined,when R_(x) is:

-   -   (a2), (a4) or (a8);    -   (a5), (a6), (a9) or (a10) and R^(1b) is selected from the group        A10);    -   (b2), (b4) or (b8);    -   (b5), (b6), (b9) or (b10) and R^(1b) is selected from the group        B10);    -   (c2);    -   (d5), (d6), (d9) or (d10) and R^(12b) is selected from the group        D10);    -   (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2),        (q2), (r2), (s2), (t1) or (u2);        a is 1 and Z is —C(O)—, when R_(x) is:    -   (a1), (a3) or (a7);    -   (a5), (a6), (a9) or (a10) and R^(1b) is selected from the groups        A8) and A9);    -   (b1), (b3) or (b7);    -   (b5), (b6), (b9) or (b10) and R^(2b) is selected from the groups        B8) or B9);    -   (c1);    -   (d1), (d2), (d3), (d4), (d7) or (d8);    -   (d5), (d6), (d9) or (d10) and R^(12b) is selected from the        groups D8) or D9);    -   (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (01), (p1),        (q1), (r1), (s1), (t2) or (u1).        Y and Y′ are bivalent radicals each independently selected from        the following meanings:        a)    -   straight or branched C₁-C₂₀ alkylene, preferably a straight or        branched C₁-C₁₀ alkylene,    -   straight or branched C₁-C₂₀ alkylene substituted with one or        more of the substituents selected from the group consisting of:        halogen atoms, hydroxy, —ONO₂ or T₂, wherein T₂ is —OC(O)(C₁-C₁₀        alkyl)-ONO₂ or —O(C₁-C₁₀ alkyl)-ONO₂, preferably Y or Y′ is a        straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;    -   cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring,        the ring being optionally substituted with one or more straight        or branched C₁-C₁₀ alkyl chains, preferably the ring being        optionally substituted with CH₃;

whereinn⁰ is an integer from 0 to 20, preferably n⁰ is 0 or 1;n¹ is 0 or 1, preferably n⁰ is 1;U is a linear or branched C₁-C₂₀ alkylene optionally substituted with a—ONO₂ group, preferably U is a linear C₁-C₁₀ alkylene or U is a linearor branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

whereinn⁰ is an integer from 0 to 20, preferably n⁰ is 0 or 1;n¹ is 0 or 1, preferably n⁰ is 1;U is a linear or branched C₁-C₂₀ alkylene optionally substituted with a—ONO₂ group, preferably U is a linear C₁-C₁₀ alkylene or U is a linearor branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ and U are as above defined;

n² is an integer from 0 to 2, preferably n² is 1;R¹³ is H or CH₃, preferably R¹³ is CH₃;Y¹ is —CH₂—CH₂— or —CH═CH—(CH₂)_(n) ^(2′)—, wherein n^(2′) is 0 or 1,preferably Y¹ is —CH═CH—(CH₂)_(n) ^(2′)- and n^(2′) is 0;T₁=—O—C(O)— or —C(O)O—, preferably T₁ is —C(O)O—;n¹ is 0 or 1, preferably n¹ is 1;U is a linear or branched C₁-C₂₀ alkylene optionally substituted with a—ONO₂ group, preferably U is a linear C₁-C₁₀ alkylene or U is a linearor branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;more preferably n² is 1, R¹³ is CH₃, Y¹ is —CH═CH—(CH₂)_(n) ^(2′)- andn^(2′) is 0, T₁ is —C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is n² is an integer from 0 to 2, preferably n⁰ is 1;R¹³ is H or CH₃, preferably R¹³ is CH₃;Y¹ is —CH₂—CH₂— or —(CH₂)_(n) ^(2′)—CH═CH—, wherein n^(2′) is 0 or 1,preferably Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 is 0 or 1, preferably n¹ is 1;U is a linear or branched C₁-C₂₀ alkylene optionally substituted with a—ONO₂ group, preferably U is a linear C₁-C₁₀ alkylene or U is a linearor branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;more preferably n² is 1, R¹³ is CH₃, Y¹ is —CH═CH—(CH₂)_(n) ^(2′)- andn^(2′) is 0, T₁ is —OC(O)— and U is a linear C₁-C₁₀ alkylene;when Y and Y′ are selected from b), c), d), e) or e′), the —ONO₂ groupof -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′Y′—ONO₂), -(T″-Y—ONO₂)and -(T″-Y′—ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is an integerfrom 1 to 6, preferably n³ is 1;

wherein:n⁴ is n⁴ is an integer from 0 to 10, preferably n⁴ is 0 or 1;n⁵ is an integer from 1 to 10, preferably n⁵ is 1;

R¹⁴, R¹⁵, R¹⁶, R¹⁷ are the same or different, and are H or straight orbranched C₁-C₄ alkyl, preferably R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are H;

wherein the —ONO₂ group is linked to

wherein n⁵ is as defined above;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 membersring, containing one or more heteroatoms selected from nitrogen, oxygen,sulphur,

and is selected from the group consisting of:

The term “C₁-C₁₀ alkyl” as used herein refers to branched or straightalkyl groups including methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl, hexyl, octyl and the like.

The term “cycloalkylene” as used herein refers to ring having from 5 to7 carbon atoms including, but not limited to, cyclopentylene,cyclohexylene optionally substituted with side chains such as straightor branched (C₁-C₁₀)-alkyl, preferably CH₃.

The term “heterocyclic” as used herein refers to saturated, unsaturatedor aromatic 5 or 6 members ring, containing one or more heteroatomsselected from nitrogen, oxygen, sulphur, such as for example pyridine,pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like.

Preferred compounds of formula (I) for the treatment of ocular diseases,in particular ocular hypertension, age-related macular degeneration,diabetic macular edema, diabetic retinopathy, hypertensive retinopathyand retinal vasculopathies, are those wherein the corticosteroid residueR is selected from the group consisting of betamethasone, fluocinoloneacetonide, triamcinolone acetonide.

Another embodiment of the invention relates to compounds of formula (I)wherein in the corticosteroid R of formula (II) R₁, R₂, R₃ and R₄ havethe following meanings:R₁ is OH in position α, R₂ —CH₃ in position β, R₃ is Cl in position αand R₄ is H; orR₁ is OH in position α, R₂ —CH₃ in position β, R₃ is F in position α andR₄ is H; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ is F and R₄ is H, R₁, R₂ and R₃ are in position α; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ and R₄ are F, R₁, R₂, R₃ and R₄ are in position α;in formula (I):a is 0 andR_(x) is selected from:

—C(O)—CH(R¹)—NH-(T′-Y—ONO₂)  (a2)

whereinR¹ of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—,2-monosubstituted benzyl, or 3-monosubstituted benzyl or4-monosubstituted benzyl wherein the substituent of the benzyl isselected from —F, —Cl, —I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;R¹ of the group A2) is selected from —CH₂—OH, —CH(CH₃)OH— or—CH₂[(C₆H₄)-(4-OH)], orR¹ of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″,—(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃;R¹ of the group A4) is selected from —CH₂—C(O)R″, —(CH₂)₂—C(O)R′″,—(CH₂)₄—C(O)R′″ wherein R′″ is OR^(5a) wherein R^(5a) is H or a linear(C₁-C₅) alkyl;T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is—C(O)—;Y is as below defined;

or R_(x) is

C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NHR^(4a)  (a4)

wherein R^(1a) of the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or—CH₂[(C₆H₄)-(4-O)—], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, orR^(1a) of the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—,—(CH₂)₄—C(O)—;

R^(4a) is H or —C(O)CH₃;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^(1a) isselected from the group A5) or A6), preferably T″ is —C(O)—;T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, whenR^(1a) is selected from the group A7);Y′ is as below defined;or R_(x) is selected from

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂)  (a5)

—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)

R^(1b)CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or  (a9)

—R^(1b)—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a10)

whereinR^(1b) of the group A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—,—C(O)—(CH₂)₄;R^(1a) is H or a (C₁-C₅) alkyl;

R^(4a) is H or —C(O)CH₃;

T is —O—, —S—, —NR′— or —O—CH(R′)—O— C(O)— wherein R′ is H or —CH₃,preferably T is —O—;T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is—C(O)—;Y and Y′ are as below defined;

or R_(x) is

—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a8)

whereinR^(1a) of the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or—CH₂[(C₆H₄)-(4-O)—], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, orR^(1a) of the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—,(CH₂)₄—C(O)—;T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^(1a) isselected from the group A5) or A6), preferably T″ is —C(O)—;T″ is —O—, —S—, —NR′— or —O—CH(R′)—O— C(O)— wherein R′ is H or —CH₃,when R^(1a) is selected from the group A7);T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is—C(O)—;Y and Y′ are as below defined;

or R_(x) is

—C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)  (b2)

whereinR² of the group B1) is selected from H, CH₃, isobutyl, isopropyl,benzyl;T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is—C(O)—;Y and Y′ are each independently selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH(CH₂)_(n) ^(2′) and n² is 0, T₁ is—C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group; when Y and Y′ areselected from d), e) or e′), the —ONO₂ group of -(T-Y—ONO₂),-(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′Y′—ONO₂), -(T′″-Y—ONO₂) and-(T′″-Y′—ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;Another embodiment of the invention relates to compounds of formula (I)wherein in the corticosteroid R of formula (II) R₁, R₂, R₃ and R₄ havethe following meanings:R₁ is OH in position α, R₂ —CH₃ in position β, R₃ is Cl in position αand R₄ is H; orR₁ is OH in position α, R₂ —CH₃ in position β, R₃ is F in position α andR₄ is H; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ is F and R₄ is H, R₁, R₂ and R₃ are in position α; orR₁ and R₂ are taken together to form a group of formula (III)

R₃ and R₄ are F, R₁, R₂, R₃ and R₄ are in position α;in formula (I):

a is 1 and Z is —C(O)—; R_(x) is

—HN—CH(R¹)—C(O)-(T-Y—ONO₂)  (a1)

whereinR¹ of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—,2-monosubstituted benzyl, or 3-monosubstituted benzyl or4-monosubstituted benzyl wherein the substituent of the benzyl isselected from —F, —Cl, —I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;orR¹ of A2) is selected from —CH₂—OH, —CH(CH₃)—OH— or —CH₂[(C₆H₄)-(4-OH)],orR¹ of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″,—(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,R¹ of the group A4) is —CH₂—C(O)R″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″wherein R′″ is OR^(5a) wherein R^(5a) is H or a linear (C₁-C₅) alkyl;T is —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— wherein R′ is H or a straightor branched C₁-C₄ alkyl, preferably T is —O—;Y is as below defined;

or R_(x) is

—HN—CH(R^(1a)-T″-Y′—ONO₂)—COOR^(3a)  (a3)

whereinR^(1a) of the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or—CH₂[(C₆H₄)O_(p)-], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, orR^(1a) of the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;R^(3a) is H or a (C₁-C₅) alkyl;T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^(1a) isselected from the group A5) or A6), preferably T″ is —C(O)—;T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straightor branched C₁-C₄ alkyl, when R^(1a) is selected from the group A7);Y′ is as below defined;

or R_(x) is

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂)  (a5)

—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)

—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or  (a9)

—R^(1b)—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a10)

whereinR^(1b) of the group A8) is selected from —O—CH(CH₃)—, —O—CH₂—,[-4-O)—(C₆H₄)]-CH₂—, orR^(1b) of the group A9) is selected from —HN—CH₂—, —HN—(CH₂)₂—,—HN—(CH₂)₃, —HN—(CH₂)₄;R^(3a) is H or a (C₁-C₅) alkyl;

R^(4a) is H or —C(O)CH₃;

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight orbranched C₁-C₄ alkyl, preferably T is —O—;T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is—C(O)—;Y and Y′ are as below defined;

or R_(x) is

—HN—CH(R^(1a)-T″-y′-ONO₂)—C(O)-(T-Y—ONO₂)  (a7)

whereinR^(1a) of the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or—CH₂[(C₆H₄)-(4-O)—], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, orR^(1a) of the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T″ is—C(O)— when R^(1a) is selected from A5) or A6);T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straightor branched C₁-C₄ alkyl, preferably T″ is —O—, when R^(1a) is selectedfrom A7);T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight orbranched C₁-C₄ alkyl, preferably T is —O—;Y and Y′ are as below defined;

or R_(x) is

—HN—CH(R²)—CH₂C(O)-(T-Y—ONO₂)  (b1)

whereinR² of the group B1) is selected from H, CH₃, isobutyl, isopropyl,benzyl;R² of the group B2) is selected from —CH₂—OH, —CH(CH₃)—OH— or—CH₂[(C₆H₄) (4-OH)], orR² of the group B3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″,—(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,R² of the group B4) is —CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″wherein R′″ is OR^(5a) wherein R^(5a) is H or a linear (C₁-C₅) alkyl;T is —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— wherein R′ is H or a straightor branched C₁-C₄ alkyl, preferably T is —O—;Y is as below defined;or R_(x) is selected from

—HN—CH(R¹²)—CH₂—O-(T′″-Y—ONO₂)  (d1)

—O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)  (d2)

whereinR¹² of the group D1) is selected from H, CH₃, isobutyl, isopropyl,benzyl, orR¹² of the group D2) is selected from —CH₂—OH, —CH(CH₃)OH— or—CH₂[(C₆H₄)-(4-OH)], orR¹² of the group D3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″,—(CH₂)₃—NHR″, —(CH₂)₄—NHR″ wherein R″ is H, orR¹² of the group D4) is —CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″wherein R′″ is OR^(5a) wherein R^(5a) is H or a linear (C₁-C₅) alkyl;T′ and T′″ are each independently selected from —C(O)— or —C(O)—X″wherein X″ is —S— or —O—, preferably T′ and T′″ are —C(O)—;Y is as below defined;or R_(x) is selected from

—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂OH  (d3)

—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NHR^(4a)  (d4)

—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂) or  (d7)

—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d8)

whereinR^(12a) of the group D5) is selected from —CH₂—O—, —CH(CH₃)—O— or—CH₂[(C₆H₄)-(4-O)—], orR^(12a) of the group D6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, orR^(12a) of the group D7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;

R^(4a) is H or —C(O)CH₃;

T″ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,preferably T′ and T′″ are —C(O)—, when R^(12a) is selected from D5) orD6);T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straightor branched C₁-C₄ alkyl, preferably T is —O—, when R^(12a) is selectedfrom D7);T′″ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,preferably T′″ is —C(O)—,Y and Y′ are as below defined;or R_(x) is selected from

—R^(12b)—CH(NHR^(4a))—CH₂—O-(T′″-Y—ONO₂)  (d5)

—R^(12b)—CH(CH₂OH)—NH-(T′-Y—ONO₂)  (d6)

—R^(12b)—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂) or  (d9)

—R^(12b)—CH(CH₂—O-T′″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d10)

whereinR^(12b) of the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—,[—O_(p)(C₆H₄)]—CH₂—, orR^(12b) of the group D9) is selected from —HN—CH₂—, —HN—(CH₄)₂—,—HN—(CH₂)₃, —HN—(CH₂)₄—;

R^(4a) is H or —C(O)—CH₃,

T′ and T′″ are each independently selected from —C(O)—, —C(O)—X″,wherein X″ is —S— or —O—, preferably T′ and T′″ are —C(O)—; Y and Y′ areeach independently selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R is CH₃, Y¹ is CH═CH(CH₂)_(n) ^(2′) and n² is 0, T₁ is C(O)O—and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is (CH₂)_(n) ^(2′)—CH═CH and n² is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;when Y and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y′—ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;Another embodiment of the present invention relates to compounds offormula (I) whereinR is the corticosteroid of formula (II) as above defined;a is 0,

R_(x) is

—C(O)—CH(R¹)—NH-(T′-Y—ONO₂)  (a2)

whereinR¹ of A1) is selected from H

T′ is —C(O)—;

Y is selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is —CH═CH—(CH₂)_(n) ^(2′)— and n^(2′) is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀alkylene substituted with a —ONO₂ group; when Y and Y′ areselected from d), e) or e′), the —ONO₂ group of -(T′-Y—ONO₂) is linkedto the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;Another embodiment relates to compounds of formula (I) wherein R is thecorticosteroid of formula (II) as above defined;

a is 0, R_(x) is

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂) or  (a5)

—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9)

wherein

R^(1b) of A10) is —C(O)—CH₂—, R^(4a) is H or —C(O)CH₃;

T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,

T′ is —C(O)— and

Y and Y′ are each independently selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH(CH₂)_(n) ^(2′) and n² is 0, T₁ isC(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;when Y and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y-f-ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;Another embodiment relates to compounds of formula (I) wherein R is thecorticosteroid of formula (II) as above defined;

a is 1 and Z is —C(O)—, R_(x) is

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂) or  (a5)

—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9)

wherein R^(1b) of A10) is —O—CH₂— or [—O_(p)—(C₆H₄)]—CH₂—,

R^(4a) is H or —C(O)CH₃,

T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,

T′ is —C(O)— and

Y and Y′ are each independently selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH(CH₂)_(n) ^(2′) and n² is 0, T₁ is—C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0;

(T₁)′=—O—C(O)—;

n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;when Y and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″-Y—ONO₂)and -(T″-Y′—ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;Another embodiment of the present invention relates to compounds offormula (I) whereinR is the corticosteroid of formula (II) as above defined;a is 0,

R_(x) is

—C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)  (b2)

wherein

R² of B1) is H, T′ is —C(O)—;

Y and Y′ are each independently selected froma)

-   -   a straight or branched C₁-C₁₀ alkylene,    -   a straight or branched C₁-C₁₀ alkylene substituted with a —ONO₂        group;

wherein:n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)— or—C(O)O—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is —CH═CH—(CH₂)_(n) ^(2′)- and n^(2′) is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein:n² is 1, R¹³ is CH₃;Y¹ is —(CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is 0; (T₁)′=—O—C(O)—;n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear or branchedC₁-C₁₀ alkylene substituted with a —ONO₂ group;when Y and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″-Y—ONO₂)and -(T″-Y′—ONO₂) is linked to the —(CH₂)— group;

—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f)

wherein T₂ is —O— or —S—, —NH—, preferably T₂ is —O—, n³ is 1 or 2;

Preferred specific embodiments of the present invention are the selectedcompounds of formula below reported:

As stated above, the invention includes also the pharmaceuticallyacceptable salts of the compounds of formula (I) and stereoisomersthereof.

Examples of pharmaceutically acceptable salts are either those withinorganic bases, such as sodium, potassium, calcium and aluminiumhydroxides, or with organic bases, such as lysine, arginine,triethylamine, dibenzylamine, piperidine and other acceptable organicamines.

The compounds according to the present invention, when they contain inthe molecule one salifiable nitrogen atom, can be transformed into thecorresponding salts by reaction in an organic solvent such asacetonitrile, tetrahydrofuran with the corresponding organic orinorganic acids.

Examples of organic acids are: oxalic, tartaric, maleic, succinic,citric acids. Examples of inorganic acids are: nitric, hydrochloric,sulphuric, phosphoric acids. Salts with nitric acid are preferred.

The compounds of the invention which have one or more asymmetric carbonatoms can exist as optically pure enantiomers, pure diastereomers,enantiomers mixtures, diastereomers mixtures, enantiomer racemicmixtures, racemates or racemate mixtures. Within the object of theinvention are also all the possible isomers, stereoisomers and theirmixtures of the compounds of formula (I).

The compounds object of the present invention are formulated in thecorresponding pharmaceutical compositions, also with belated release,for parenteral, oral and topic use, such as for example sublingual,inhalatory, suppository, transdermal, enema, according to the well knowntechniques in the art, together with the usual excipients; see forexample the publication “Remington's Pharmaceutical Sciences” 15^(th)Ed.

The amount on a molar basis of the active principle in said compositionsis generally the same, or lower than that of the corresponding precursordrug.

The daily administrable doses are those of the precursor drugs, oroptionally lower. The precursor daily doses can be found in thepublications of the field, such for example in the “Physician's Deskreference”.

The present invention compounds are used in particular for the treatmentof ocular disease therapies such as ocular hypertension, age-relatedmacular degeneration, diabetic macular edema, diabetic retinopathy,hypertensive retinopathy and retinal vasculopathies.

Synthesis Procedure

1) The compound of general formula (I) as above defined wherein a isequal to 0, the radical R_(x) is selected from (a2), (a4), (a8), (b2),(b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (12), (m2), (n2), (o2),(p2), (q2), (r2), (s2), (t2), (u2), (v2), can be obtained:1-i) by reacting a compound of (IIa)

wherein R₁, R₂, R₃, R₄, are as above defined, with a compound of formula(Ia)

W—X₁  (Ia)

wherein W is —OH, Cl, O—R_(a) wherein R_(a) is pentafluorophenyl,4-nitrophenyl or —(N-succimidyl), X₁ is as below defined, to obtain thecompound of formula (IIa′)

wherein R₁, R₂, R₃, R₄, are as above defined and X₁ is as below defined,X₁ is a radical having the following meaning:

—C(O)—CH(R^(1′))—NH-(T′-Y-Q)  (a2′)

wherein R^(1′) is selected fromA1) as defined above orA2′) —CH₂—SP¹, —CH₂—OP¹, —CH(CH₃)—OP¹, —CH₂[(C₆H₄)-4-OP¹],—CH₂-[(C₆H₃)-(3,5-diiodo)-4-OP¹], —CH₂-[(C₆H₃)-3-nitro-4-OP¹] orA3′) —CH₂—NHR″″, (CH₂)₂—NHR″″, (CH₂)₃—NHR″″, —(CH₂)₄—NHR″″, wherein R″″is P³ or —C(O)CH₃ or

wherein R^(5a) is as defined above;

A4′) —CH₂—C(O)R′″″, —(CH₂)₂—C(O)R′″″, —(CH₂)₄—C(O)R″″

wherein R′″″ is P², —OR^(5a) or

wherein R^(5a) is as above defined;

—C(O)—CH(R^(1a)-T″-Y′-Q)-NHR^(4a′)  (a4′)

—C(O)—CH(R^(1a)-T″-Y′-Q)-NH-(T′-Y-Q)  (a8′)

wherein R^(1a) is as defined above;

—C(O)—CH₂—CH(R^(2′))—NH-(T′-Y-Q)  (b2′)

wherein R^(2′) is selected fromB1) as defined above or

B2′) —CH(CH₃)—OP¹, —CH₂—[(C₆H₄)-4-OP¹];

B3′) —CH₂—NHR″″, —(CH₂)₂—NHR″″, —(CH₂)₃—NHR″″, —(CH₂)₄—NHR″″, whereinR″″ is as above defined;B4′) —CH₂—C(O)—R′″″, —(CH₂)₂—C(O)—R′″″, —(CH₂)₄—C(O)—R′″″ wherein R′″″is as above defined;

R^(4a′) is P³ or —C(O)—CH₃ or

—C(O)—CH₂—CH(R^(2a)-T″-Y′-Q)-NHR^(4a′)  (b4′)

—C(O)—CH₂—CH(R^(2a)-T″-Y′-Q)-NH-(T′-Y-Q)  (b8′)

wherein R^(2a) and R^(4a) are as defined above;

—C(O)—(CH₂)_(b)—NH-(T′-Y-Q);  (c2′)

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, b, c, d, e and f are asabove defined;wherein P¹ is a hydroxyl or thiol protecting group such as silyl ethers,such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and thosedescribed in T. W. Greene “Protective groups in organic synthesis”,Harvard University Press, 1980, P² is a carboxylic protecting group suchas tert-butyl ester and those described in T. W. Greene “Protectivegroups in organic synthesis”, Harvard University Press, 1980, P³ is aamino protecting group such as Boc, Fmoc or those described in T. W.Greene “Protective groups in organic synthesis”, Harvard UniversityPress, 1980,T, T′, T″, Y and Y′ are as above defined,Q is independently —ONO₂ or Z₂ wherein Z₂ is selected from the groupconsisting of: a chlorine atom, a bromine atom, a iodine atom, a mesylgroup or a tosyl group, and1-ii) when Q is Z₂, by converting the compound obtained in the step 1-i)into nitro derivative by reaction with a nitrate source such as silvernitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesiumnitrate, calcium nitrate, iron nitrate, zinc nitrate ortetraalkylammonium nitrate (wherein alkyl is C₁-C₁₀ alkyl) in a suitableorganic solvent such as acetonitrile, tetrahydrofurane, methyl ethylketone, ethyl acetate, DMF, the reaction is carried out, in the dark, ata temperature from room temperature to the boiling temperature of thesolvent. Preferred nitrate source is silver nitrate and 1-iii)optionally deprotecting the compounds obtained in step 1-i) or 1-ii) asdescribed in T. W. Greene “Protective groups in organic synthesis”,Harvard University Press, 1980, 2^(nd) edition. Fluoride ion is thepreferred method for removing silyl ether protecting group.Trifluoroacetic acid or anhydrous inorganic acid are the preferredmethod for removing Boc protecting group, anhydrous organic or inorganicacid is the preferred method for removing trityl protecting group.Organic base such as piperidine is the preferred method for removingFmoc protecting group. Aqueous or anhydrous organic or inorganic acid isthe preferred method for removing t-butyl ester protecting group.1-i-1) The reaction of a compound of formula (Ia) wherein W=—OH and X₁is as above defined, with a compound of formula (IIa) may be carried outin presence of a condensing agent as dicyclohexylcarbodiimide (DCC),N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC)N,N′-carbonyldiimidazole (CDI), in the presence or not of a base as forexample as N,N-dimethylamino pyridine (DMAP).

The reaction is carried out in an inert organic dry solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, apolyhalogenated aliphatic hydrocarbon at a temperature from −20° C. and50° C. The reaction is completed within a time range from 30 minutes to36 hours.

1-i-2) The reaction of a compound of formula (Ia) wherein W=—O—R_(a)wherein R_(a) and X₁ are as above defined, with a compound of formula(IIa) may be carried out in presence of a catalyst, such asN,N-dimethylamino pyridine (DMAP) or in the presence of DMAP and a Lewisacid such as Sc(OTf)₃ or Bi(OTf)₃.

The reaction is carried out in an inert organic solvent such asN,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, apolyhalogenated aliphatic hydrocarbon at a temperature from −20° C. and40° C. The reaction is completed within a time range from 30 minutes to36 hours.

1-i-3) The reaction of a compound of formula (Ia) wherein W=—Cl, and X₁is are as above defined, with a compound of formula (IIa) may be carriedout in presence of of an organic base such as N,N-dimethylamino pyridine(DMAP), triethylamine, pyridine. The reaction is carried out in an inertorganic solvent such as N,N′-dimethylformamide, tetrahydrofuran,benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at atemperature from −20° C. and 40° C. The reaction is completed within atime range from 30 minutes to 36 hours.

The compounds of formula (IIa) are commercially available.

1a) The compounds of formula (Ia) wherein W is —OH, T′ and T″ are C(O),and X₁ is the radical selected from (a2′), (a4′), (b2′), (b4′), (c2′),(e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′),(q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R′ is selected fromA1), A2′), A3′), A4′), R^(1a) is selected from A5) or A6), R^(2a) isselected from B5) or B6) and R^(2′) is selected from B1), B2′), B3′),B4′) and Y, Y′ and R^(4a′) are as above defined, can be obtained1a-i) by reacting a compound of formula (IIIa)

P²—X₂  (IIIa)

wherein P² is as above defined, X₂ is a radical having the followingmeaning

—C(O)—CH(R^(1′))—NH₂  (a2″)

—C(O)—CH(R^(1a)—H)—NHR^(4a′)  (a4″)

wherein R^(1′) is selected from A1), A2′), A3′), A4′), R^(1a) isselected from A5) or A6) and R^(4a′) is as defined above

—C(O)—CH₂—CH(R^(2′))—NH₂,  (b2″)

—C(O)—CH₂—CH(R^(2a)—H)—NHR^(4a′)  (b4″)

wherein R^(2′) is selected from B1), B2′), B3′), B4′), R^(2a) isselected from B5) or B6) and R^(4a′) is as defined above,

—C(O)—(CH₂)_(b)NH₂,  (c2″)

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, b, c, d, e and f are asabove defined;with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁ is OH or O—R_(a) and R_(a) and Q are as above defined, y isthe radical Y when X₂ is selected from (a2′), (b2′), (c2′), (e2′),(f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′),(r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X₂ isselected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and1a-ii) when Q is Z₂, by converting the compound obtained in the step1a-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1a-iii) optionally deprotecting the compounds obtained in step 1a-i) or1a-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P² and X₂ are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y, Qare as above defined, may be carried out as described in 1-i-1) or inpresence of other known condensing reagents such as0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU).

The reaction of a compound of formula (IIIa) wherein P² and X₂ are asabove defined, with a compound of formula (IVa) wherein W₁ is O—R_(a),y, Q are as above defined, may be carried as described in 1-i-2).

The compounds of formula (IIIa) are commercially available or can beobtained as known in the literature.

The compounds of formula (IVa) wherein W₁ is OH, y and Q are as abovedefined, can be obtained from the corresponding alcohols of formulaHOOC-y-OH (IVb) by reaction with nitric acid and acetic anhydride in atemperature range from −50° C. to 0° C. or from the correspondingderivatives of formula HOOC-y-Z₂ (IVc) wherein Z₂ is as above defined,by reaction with a nitrate source as above described. Alternatively thereaction with AgNO₃ can be performed under microwave irradiation insolvents such acetonitrile or THF at temperatures in the range betweenabout 100-180° C. for time range about 1-60 min.

The compounds of formula (IVb) are commercially available.

The compounds of formula (IVc) are commercially available or can beobtained as known in the literature.

The compounds of formula (IVa) wherein W₁ is O—R_(a), y, Q are as abovedefined, can be obtained from the corresponding acids of formula (IVa)wherein W₁ is OH as known in the literature.

The compounds of formula (Ia) wherein W=Cl or O—R_(a), X₁ is selectedfrom (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′),(i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′),(u2′), (v2′), wherein R′ is selected from A1), A2′), A3′), A4′), R^(1a)is selected from A5) or A6), R^(2a) is selected from B5) or B6) andR^(2′) is selected from B1), B2′), B3′), B4′), and wherein Y, Y′ and Qare as above defined and T′ and T″ are C(O), can be obtained from thecorresponding acids (Ia) wherein W is —OH as known in the literature.

1b) The compounds of formula (Ia) wherein W is —OH, X₁ is the radicalselected from (a2′), (a4′), (b2′), (b4′) (c2′), (e2′), (f1′), (g2′),(h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′),(t2′), (u2′), (v2′), wherein R′ is selected from A1), A2′), A3′), A4′),R^(1a) is selected from A5) or A6), R^(2a) is selected from B5) or B6)and R^(2′) is selected from B1), B2′), B3′), B4′), Y and Y′ are as abovedefined, T′ and T″ are C(O)—X″, wherein X″ is —O— or —S— can be obtained1b-i) by reacting a compound of formula (IIIa)

P²—X₂  (IIIa)

wherein P² and X₂ are as defined above, with a compound of formula (IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), X″ and Q are as above defined, y is the radical Y when X₂is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′),(12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′),(v2′), and y is the radical Y′ when X₂ is selected from (a4′) or (b4′),wherein Y and Y′ are as above defined, and1b-ii) when Q is Z₂, by converting the compound obtained in the step1b-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1b-iii) optionally deprotecting the compounds obtained in step 1b-i) or1b-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P² and X₂ are asabove defined, with a compound of formula (IVd) wherein R_(a), X″, y andQ are as above defined, may be carried out as described in 1-i-2)

The compounds of formula (IVd) wherein R_(a), X″, y, Q are as abovedefined, can be obtained from the compounds of formula HX″-y-Q (IVe)wherein X″, y, Q are as above defined, as known in literature.

The compound of formula (IVe) are commercially available or are known inliterature.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ isselected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′),(h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′),(t2′), (u2′), (v2′), wherein R^(1a) is selected from A1), A2′), A3′),A4′), R^(1a) is selected from A5) or A6), R^(2a) is selected from B5) orB6) and R^(2′) is selected from B1), B2′), B3′), B4′), Y, Y′ and Q areas above defined, T′ and T″ are C(O)—X″ wherein X″ is O or S, can beobtained from the corresponding acids (Ia) wherein W is —OH as known inthe literature.

1c) The compounds of formula (Ia) wherein W is —OH and X₁ is a radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A5) orA6), R^(2a) is selected from B5) or B6), Q is as above defined, T′ andT″ are C(O), Y and Y′ are the same and are as above defined, can beobtained1c-i) by reacting a compound of formula (IIIb),

P²—X₃  (IIIb)

wherein P² is as above defined, X₃ is the radical of formula

—C(O)—CH(R^(1a)—H)—NH₂  (a8″)

—C(O)—CH₂—CH(R^(2a)—H)—NH₂  (b8″)

wherein R^(1a) is selected from A5) or A6), R^(2a) is selected from B5)or B6), with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁ and Q are as above defined, wherein y is the radical Y or Y′,wherein Y and Y′ are as above defined, and1c-ii) when Q is Z₂, by converting the compound obtained in the step1c-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1c-iii) optionally deprotecting the compounds obtained in step 1c-i) or1c-ii) as above described.

The reaction of a compound of formula (IIIb) wherein P² and X₃ are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y andQ are as above defined, may be carried out as described in 1a-i) using aratio (IIIb)/(IVa) 1:2. The reaction of a compound of formula (IIIb)wherein P² and X₃ are as above defined, with a compound of formula (IVa)wherein W₁ is OR_(a), y and Q are as above defined, may be carried outas described in 1-i-2) using a ratio (IIIb)/(IVa) 1:2.

The compounds of formula (IIIb) are commercially available or can beobtained as known in the literature.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is theradical selected from (a8′) or (b8′) wherein R^(1a) is selected from A5)or A6), R^(2a) is selected from B5) or B6) and wherein Y, Y′ and Q areas above defined and T′ and T″ are C(O), can be obtained from thecorresponding acids (Ia) wherein W is —OH as known in the literature.

1d) The compounds of formula (Ia) wherein W is —OH, X₁ is the radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A5) orA6), R^(2a) is selected from B5) or B6), Q, Y and Y′ are as abovedefined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ isC(O), can be obtained1d-i) by reacting a compound of formula (Ib)

P²—X₃,  (Ib)

wherein P² is as above defined, X₃, is the radical of formula

—C(O)—CH(R^(1a)—H)—NH-(T′-Y-Q)  (a8″)

—C(O)—CH₂—CH(R^(2a)—H)—NH-(T′-Y-Q)  (b8′″)

wherein R^(1a) is selected from A5) or A6), R^(2a) is selected from B5)or B6), with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁ and Q are as above defined, wherein y is the radical Y′,wherein Y′ is as above defined, and1d-ii) when Q is Z₂, by converting the compound obtained in the step1d-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1d-iii) optionally deprotecting the compounds obtained in step 1d-i) or1d-ii) as above described.

The reaction of a compound of formula (Ib) wherein P² and X₃, are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y andQ are as above defined, may be carried out as described in 1a-i).

The reaction of a compound of formula (Ib) wherein P² and X₃, are asabove defined, with a compound of formula (IVa) wherein W₁ is OR_(a), yand Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P² and X₃, are asabove defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P² and X₃, are asabove defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R_(a)′, X₁ is theradical selected from (a8′) or (b8′) wherein R^(1a) is selected from A5)or A6), R^(2a) is selected from B5) or B6) and wherein Q, Y and Y′ areas above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined,T″ is C(O), can be obtained from the corresponding acids (Ia) wherein Wis —OH as known in literature.

1e) The compounds of formula (Ia) wherein W is —OH, X₁ is the radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A5) orA6), R^(2a) is selected from B5) or B6), Q is as above defined, Y and Y′are the same and are as above defined, T′ and T″ are C(O)—X″— wherein X″is as above defined, can be obtained 1e-i) by reacting a compound offormula (IIIb)

P²—X₃  (IIIb)

wherein P² and X₃ are as above defined, with a compound of formula (IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and Q are as above defined, wherein y is the radical Y′,wherein Y′ is as above defined, and1e-ii) when Q is Z₂, by converting the compound obtained in the step1e-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1e-iii) optionally deprotecting the compounds obtained in step 1e-i) or1e-ii) as above described.

The reaction of a compound of formula (IIIb) wherein P² and X₃ are asabove defined, with a compound of formula (IVd) wherein R_(a), y and Qare as above defined, may be carried out as described in 1-i-2) using aratio (IIIb)/(IVd) 1:2.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is theradical selected from (a8′) or (b8′) wherein R^(1a) is selected from A5)or A6), R^(2a) is selected from B5) or B6) and wherein Y and Y′, Q is asabove defined and T′ and T″ are C(O)—X″— wherein X″ is as above defined,can be obtained from the corresponding acids (Ia) wherein W is —OH asknown in literature.

1f) The compounds of formula (Ia) wherein W is —OH, X₁ is selected from(a8′) or (b8′), wherein R^(1a) is selected from A5) or A6), R^(2a) isselected from B5) or B6), Q, Y and Y′ are as above defined, T′ is C(O)or C(O)—X″ wherein X″ is as above defined, T″ is C(O)—X″, can beobtained1f-i) by reacting a compound of formula (Ib)

P²—X₃,  (Ib)

wherein X₃, and P² are as above defined, with a compound of formula(IVd)

W₁—O—C(O)—X″-y-Q  (IVd)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and1f-ii) when Q is Z₂, by converting the compound obtained in the step1f-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1f-iii) optionally deprotecting the compounds obtained in step 1f-i) or1f-ii) as above described.

The reaction of a compound of formula (Ib) wherein P² and X₃, are asabove defined, with a compound of formula (IVd) wherein W₁ is OH, y andQ are as above defined, may be carried out as described in 1a-i).

The reaction of a compound of formula (Ib) wherein P² and X₃, are asabove defined, with a compound of formula (IVd) wherein W₁ is OR_(a), yand Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P² and X₃, are asabove defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P² and X₃, are asabove defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R_(a)′, X₁ is aradical selected from (a8′) or (b8′) wherein R^(1a) is A5) or A6),R^(2a) is B5) or B6) and wherein Q, Y and Y′ are as above defined, T′ isC(O) or C(O)—X″ and T″ is C(O)—X, wherein X″ is as above defined, can beobtained from the corresponding acids (Ia) wherein W is —OH as known inliterature.

1g) The compounds of formula (Ia) wherein W is —OH, X₁ is a radical isselected from (a8′) or (b8′), wherein R^(1a) is selected from A5), A6),R^(2a) is selected from B5), B6), Q, Y and Y′ are as above defined, T′is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O)—NR′wherein R′ is above defined, can be obtained1g-i) by reacting a compound of formula (Ib)

P²—X₃,  (Ib)

wherein P² and X₃, are as above defined, with a compound of formula

R_(a)—O—(O)C—NR′-y-Q  (IVf)

wherein R_(a), R′ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and1g-ii) when Q is Z₂, by converting the compound obtained in the step1g-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1g-iii) optionally deprotecting the compounds obtained in step 1g-i) or1g-ii) as above described.

The reaction of a compound of formula (Ib) wherein P² and X₃, are asabove defined, with a compound of formula (IVf) wherein R_(a), R′, y, Qare as above defined, may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), wherein P² and X₃, areas above defined, are obtained as described in 1a-i), 1a-ii).

The compounds of formula (Ib) wherein T′ is C(O)—X″, wherein P² and X₃,are as above defined, are obtained as described in 1b-i), 1b-ii).

The compounds of formula (IVf) wherein R′, y and Q are as above defined,can be obtained from the compounds of formula HR′N-y-Q (IVg) by reactionwith a chloroformate as known in the literature.

The compounds of formula (IVg) wherein y is as above defined and Q is Z₂is commercially available, the compounds of formula (IVg) wherein y isas above defined and Q is —ONO₂ may be obtained from the compound offormula P³—R′N-y-ONO₂ (IVh) wherein P³ is as above defined bydeprotection of amino group as known in literature. The compounds offormula (IVh) wherein P³, y are as above defined may be obtained fromthe alcohol P³—R′N-y-OH (IVi) by reacting with tetraalkylammoniumnitrate as already described for analogous compounds. The compounds offormula (IVi) are commercially available or known in literature.Alternatively the compounds of formula (IVh) wherein P³, y are as abovedefined may be obtained from the corresponding compounds of formulaP³—R′N-y-Z₂ (IVl) wherein P³, y, Z₂ are as above defined, by reactionwith a nitrate source as above described.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is aradical selected from (a8′) or (b8′) wherein R^(1a) is selected from A5)or A6), R^(2a) is selected from B5) or B6) and wherein Y, Y′ and Q areas above defined and T′ is C(O) or C(O)—X″, T″ is C(O)—NR′—, wherein X″and R′ are as above defined, can be obtained from the correspondingacids (Ia) wherein W is —OH as known in literature.

1h) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Q, Y and Y′ are as above defined, T′ isC(O) or C(O)—X″, T″ is X″ wherein X″ is above defined, can be obtained1h-i) by reacting a compound of formula (Ie),

P²—X₅  (Ie)

wherein P² is defined above, X₅ is the radical of formula

—C(O)—CH(R^(1a)—OH)—NH-(T′-Y-Q)  (a8′″)

—C(O)—CH₂—CH(R^(2a)—OH)—NH-(T′-Y-Q)  (b8′″)

wherein R^(1a) is selected from A7), R^(2a) is selected from B7), with acompound of formula (IVe)

HX″-y-Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and1h-ii) when Q is Z₂, by converting the compound obtained in the step1h-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1h-iii) optionally deprotecting the compounds obtained in step 1h-i) or1h-ii) as above described.

The reaction of a compound of formula (Ie) wherein P² and X₅ are asabove defined, with a compound of formula (IVe) wherein y, X″ and Q areas above defined, may be carried out as described in 1-i-1).

The compounds of formula (Ie) wherein T′ is C(O), wherein P² and X₅ areas above defined, are obtained as described in 1a-i), 1a-ii).

The compounds of formula (Ie) wherein T′ is C(O)—X″, wherein P² and X₅are as above defined, are obtained as described in 1b-i), 1b-ii).

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is aradical selected from (a8′) or (b8′) wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y, Y′ and Q are as abovedefined, T′ is C(O) or C(O)—X″, and T″ is X″ wherein X″ is as abovedefined, can be obtained from the corresponding acids (Ia) wherein W is—OH as known in literature.

1i) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Q, Y and Y′ are as above defined, T′ isC(O) or C(O)—X″ wherein X″ is as above defined, T″ is —NR′ wherein R′ isabove defined, can be obtained1i-i) by reacting a compound of formula (Ie),

P²—X₅  (Ie)

wherein is P² and X₅ are defined above, with a compound of formula (IVg)

HR′N-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and1i-ii) when Q is Z₂, by converting the compound obtained in the step1i-i) into nitro derivative by reaction with a nitrate source such abovedescribed and1i-iii) optionally deprotecting the compounds obtained in step 1i-i) or1i-ii) as above described.

The reaction of a compound of formula (Ie) wherein P² and X₅ are asabove defined, with a compound of formula (IVg) wherein R′, y and Q areas above defined, may be carried out as described in 1a-i).

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is theradical selected from (a8′) or (b8′) wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y, Y′ and Q are as abovedefined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is—NR′ wherein R′ is as above defined can be obtained from thecorresponding acids (Ia) wherein W is —OH as known in literature

1l) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Q, Y and Y′ are as above defined, T′ isC(O) or C(O)—X″ wherein X″ is as above defined, T″ is —O—CH(R′)—O—C(O)—,wherein R′ is as above defined, can be obtained1l-i) by reacting a compound of formula (Ie),

P²—X₅  (Ie)

wherein is P² and X₅ are defined above, with a compound of formula (IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, Hal is an halogen atom, y is theradical Y′, wherein Y′ is as above defined, and1l-ii) when Q is Z₂, by converting the compound obtained in the step1l-i) into nitro derivative by reaction with a nitrate source such abovedescribed and1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or1l-ii) as above described.

The reaction of a compound of formula (Ie) wherein P⁵ and X₅ are asabove defined, with a compound of formula (IVm) wherein y, Q, R′ are asabove defined may be carried out in the presence of a inorganic ororganic base in an aprotic polar/non-polar solvent such as DMF, THF orCH₂Cl₂ at temperatures range between 0° to 100° C. or in a double phasesystem H₂O/Et₂O at temperatures range between 20° to 40° C.

The compounds of formula (IVm) wherein y, Q, R′ are as above defined,Hal is an halogen atom may be obtained by reacting a compoundR′—CH₂—CHO, commercially available, with a compound of formulaHal-(O)C-y-Q (IVn), wherein y and Q are as above defined, Hal is achlorine atom and ZnCl₂ as known in literature.

The compounds of formula (IVn) may be obtained as known in literature.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is aradical selected from (a8′) or (b8′) wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y, Y′, and Q are as abovedefined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is—O—CH(R′)—O—C(O)— wherein R′ is as above defined can be obtained fromthe corresponding acids (Ia) wherein W is —OH as known in literature.

1m) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a8′) or (b8′), wherein R^(1a) is selected from A7),R^(2a) is B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″wherein X″ is as above defined, T″ is —O—CH(R′)—O—C(O)O—, wherein R′ isas above defined, can be obtained1m-i) by reacting a compound of formula (Ie),

P²—X₅  (Ie)

wherein is P² and X₅ are defined above, with a compound of formula (IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, Hal is an halogen atom, and1l-ii) when Q is Z₂, by converting the compound obtained in the step1l-i) into nitro derivative by reaction with a nitrate source such abovedescribed and1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or1l-ii) as above described.

The reaction of a compound of formula (Ie) wherein P² and X₅ are asabove defined, with a compound of formula (IVo) wherein y, R′, Q, Halare as above defined may be carried out as described in 1l-i).

The compounds of formula (IVo) wherein y, R′, Q are as above defined,may be obtained by reacting the compounds of formulaHal-(R′)CH—OC(O)Hal, wherein Hal is as above defined, commerciallyavailable, with a compound of formula HO-y-Q (IVe) wherein y, Q are asabove defined, in the presence of a inorganic or organic base in anaprotic polar or in an aprotic non-polar solvent such as DMF, THF orCH₂Cl₂ at temperatures range between 0° to 65° C.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is aradical selected from (a8′) or (b8′) wherein R^(1a) selected from A7),R^(2a) selected from B7) and wherein Y, Y′ and Q are as above defined,T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is—O—CH(R′)—O—C(O)O—, may be obtained from the corresponding acids (Ia)wherein W is —OH as known in literature.

1n) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a4′) or (b4′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Y′, Q and R^(4a′) are as above defined andT″ is X″ wherein X″ is as above defined, can be obtained1n-i) by reacting a compound of formula (IIIc)

P²—X₅,  (IIIc)

wherein P² is defined above, X_(5′) is

—C(O)—CH(R^(1a)—OH)—NHR^(4a′)  (a4″)

—C(O)—CH₂—CH(R^(2a)—OH)—NHR^(4a′)  (b4″)

wherein R^(1a) is selected from A7), R^(2a) is selected from B7) and P³is as above defined,with a compound of formula (IVe)

HX″-y-Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and1n-ii) when Q is Z₂, by converting the compound obtained in the step1n-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1n-iii) optionally deprotecting the compounds obtained in step 1n-i) or1n-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X_(5′) and P² areas above defined, with a compound of formula (IVe) wherein X″, y, Q areas above defined may be carried out as described in 1-i-1).

The compounds of formula (IIIc) wherein X_(5′) and P² are as abovedefined, are commercially available or can be obtained as known in theliterature.

The compounds of formula (Ia) wherein W is —Cl or O—R_(a), X₁ is aradical selected from (a4′) or (b4′), wherein R^(1a) is selected fromA7), R^(2a) is selected from B7), Y′ and Q are as above defined, T″ isX″, wherein X″ is as above defined, can be obtained from thecorresponding acids (Ia) wherein W is —OH as known in literature.

1o) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a4′) or (b4′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Y′, Q and R^(4a′) are as above defined andT″ is —NR′ wherein R′ is as above defined, can be obtained1o-i) by reacting a compound of formula (IIIc)

P²—X₅,  (IIIc)

wherein P² and X₅, are as above defined, with a compound of formula(IVg)

HR′N-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, and 1o-ii)when Q is Z₂, by converting the compound obtained in the step 1o-i) intonitro derivative by reaction with a nitrate source as above describedand1o-iii) optionally deprotecting the compounds obtained in step 1o-i) or1o-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X₅, and P² are asabove defined, with a compound of formula (IVg) wherein R′, y and Q areas above defined may be carried out as described in 1a-i).

The compounds of formula (Ia) wherein W is —Cl or —OR_(a), X₁ is aradical selected from (a4′) or (b4′), wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y′, Q are as above definedand T″ is —NR′ wherein R′ is as above defined, can be obtained may beobtained from the corresponding acids (Ia) wherein W=—OH as known inliterature.

1p) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a4′) or (b4′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Y′, Q and R^(4a′) are as above defined andT″ is —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained1p-i) by reacting a compound of formula (IIIc)

P²—X₅,  (IIIc)

wherein P² and X₅, are as above defined, with a compound of formula(IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, Hal is an halogen atom and1p-ii) when Q is Z₂, by converting the compound obtained in the step1p-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1p-iii) optionally deprotecting the compounds obtained in step 1p-i) or1p-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P² and X₅, are asabove defined, with a compound of formula (IVm) wherein R′, y, Q, Halare as above defined, may be carried out as described in 1l-1).

The compounds of formula (Ia) wherein W is —Cl or OR_(a), X₁ is aradical selected from (a4′) or (b4′), wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y and Q are as abovedefined and T″ is the group —O—CH(R′)—O—C(O), wherein R′ is as abovedefined, can be obtained from the corresponding acids (Ia) wherein W=—OHas known in literature.

1q) The compounds of formula (Ia) wherein W is —OH, X₁ is a radicalselected from (a4′) or (b4′), wherein R^(1a) is selected from A7),R^(2a) is selected from B7), Y′, Q and R^(4a′) are as above defined andT″ is —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, can beobtained1q-i) by reacting a compound of formula (IIIc)

P²—X₅,  (IIIc)

wherein P² and X₅, are as above defined, with a compound of formula(IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, Hal is an halogen atom and1q-ii) when Q is Z₂, by converting the compound obtained in the step1q-i) into nitro derivative by reaction with a nitrate source as abovedescribed and1q-iii) optionally deprotecting the compounds obtained in step 1q-i) or1q-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P² and X₅, are asabove defined, with a compound of formula (IVo) wherein R′, y, Q, Halare as above defined, may be carried out as described in 1l-1).

The compounds of formula (Ia) wherein W is —Cl or OR_(a), X₁ is aradical selected from (a4′) or (b4′), wherein R^(1a) is selected fromA7), R^(2a) is selected from B7) and wherein Y, Q, are as above definedand T″ is the group —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined,can be obtained may be obtained from the corresponding acids (Ia)wherein W=—OH as known in literature.

2) The compound of general formula (I) as above defined wherein a isequal to 1, the radical R_(x) is the radical selected from (a2), (a4),(a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (12), (m2),(n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is —CH(R′)—O—wherein R′ is selected from H or straight or branched C₁-C₄ alkyl, canbe obtained:2-i) by reacting a compound of formula (IIa)

R—OH  (IIa)

wherein R is as above defined with a compound of formula (If)

Hal-CH(R′)—O—X₁  (If)

wherein Hal is an halogen atom, R′ and X₁ are as above defined and2-ii) when Q is Z₂, by converting the compound obtained in the step 2-i)into nitro derivative by reaction with a nitrate source as abovedescribed and2-iii) optionally deprotecting the compounds obtained in step 2-i) or2-ii) as above described.

The reaction of a compound of formula (If) wherein X₁ and R′ are asabove defined, with a compound of formula (IIa) wherein R is as abovedefined, may be carried out as described in 1l-i).

The compounds of formula (If) are obtained by reacting a compoundR′—CHO, wherein R′ is as above defined with compounds of formula (Ia)

W—X₁  (Ia)

wherein W is a chlorine atom, X₁ is as above defined, and ZnCl₂ as knownin literature.3) The compound of general formula (I) as above defined wherein a isequal to 1, the radical R_(x) is selected from (a1), (a3), (a7), (b1),(b3), (b7), (c1), (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (01),(p1), (q1), (r1), (s1), (t1), (u1), (v1), Z is C(O), can be obtained3-i) by reacting a compound of formula

R—C(O)—O—R_(a)  (IIb)

wherein R and R_(a) are as above defined, with a compound of formula(Ig)

H—X₂  (Ig)

wherein X₂ is a radical having the following meanings:

—HN—CH(R^(1′))—C(O)-(T-Y-Q)  (a1′)

—HN—CH(R^(1a)-T″-Y′-Q)-COOR^(3a′)  (a3′)

—HN—CH(R^(1a)-T″-Y′-Q)-C(O)-(T-Y-Q)  (a7′)

—HN—CH(R^(2′))—CH₂C(O)-(T-Y-Q)  (b1′)

—HN—CH(R^(2a)-T″-Y′-Q)-CH₂COOR^(2a′)  (b3′)

—HN—CH(R^(2a-)T″-Y′-Q)-CH₂—C(O)-(T-Y-Q)  (b7′)

wherein R^(1′), R^(1a), R^(2′), R^(2a) are as above defined R^(3a′) isselected from P², —OR^(5a) or

wherein R^(5a) is as above defined;

—HN—(CH₂)_(b)—C(O)-(T-Y-Q);  (c1′)

wherein T, T″, Y and Y′ are as above defined,3-ii) when Q is Z₂, by converting the compound obtained in the step 3-i)into nitro derivative by reaction with a nitrate source such abovedescribed and3-iii) optionally deprotecting the compounds obtained in step 3-i) or3-ii) as above described.

The reaction of a compound of formula (IIb) wherein R and R_(a) are asabove defined, with a compound of formula (Ig) wherein X₁ is as abovedefined, may be carried out as described in 1-i-2).

The compounds of formula R—C(O)—O—R_(a), (IIb) wherein R and R_(a) areas above defined, are obtained from the compounds R—H (IIa) by reactionwith the compounds of formula Cl—C(O)—O—R_(a) wherein R_(a) is as abovedefined, as known in literature.

3a) The compounds of formula (Ig) wherein X₂ is selected from (a1′),(a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′),(m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′),wherein R′ is selected from A1), A2′), A3′), A4′), R^(1a) is selectedfrom A7), R^(2a) is selected from B7) and R^(2′) is selected from B1),B2′), B3′), B4′), Y and Y′ are as above defined, T and T″ are X″ whereinX″ is as above defined may be obtained3a-i) by reacting a compound of formula (IIIe),

P³—X₆  (IIIe)

wherein P³ is as above defined, X₆ is a radical having the followingmeanings:

—HN—CH(R^(1′))—C(O)—OH  (a1″)

—HN—CH(R^(1a)—OH)—COOR^(3a′)  (a3″)

—HN—CH(R^(2′))—CH₂C(O)—OH  (b1″)

—HN—CH(R^(2a)—OH)—CH₂COOR^(3a′)  (b3″)

wherein R^(1′) is selected from A1), A2′), A3′), A4′), selected fromA7), R^(2a) is selected from B7) and R^(2′) is selected from B1), B2′),B3′), B4′), and R^(3a′) is defined above

—HN—(CH₂)_(b)—C(O)—OH;  (c1″)

with a compound of formula (IVe)

HX″-y-Q  (IVe)

wherein Q and X″ are as above defined y is the radical Y when X₆ isselected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′),(11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and(v1′), y is the radical Y′ when X₆ is selected from (a3′) and (b3′),wherein Y and Y′ are as defined above, and3a-ii) when Q is Z₂, by converting the compound obtained in the step3a-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3a-iii) optionally deprotecting the compounds obtained in step 3a-i) or3a-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P³ and X₆ are asabove defined, with a compound of formula (IVe), wherein y, Q and X″ areas above defined, may be carried out as described in 1-i-1).

The compounds of formula (IIIe) are commercially available or can beobtained as known in the literature.

3b) The compounds of formula (Ig) wherein X₂ is selected from (a1′),(a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′),(m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′),wherein R′ is selected from A1), A2′), A3′), A4′), R^(1a) is selectedfrom A7), R^(2a) is selected from B7) and R^(2′) is selected from B1),B2′), B3′), B4′), and R^(3a′), Y and Y′ are as above defined, T and T″are —NR′ wherein R′ is as above defined may be obtained3b-i) by reacting a compound of formula (IIIe),

P³—X₆  (IIIe)

wherein P³ and X₆ are as above defined, with a compound of formula

HR′N-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y when X₆ isselected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′),(11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and(v1′), y is the radical Y′ when X₆ is selected from (a3′) and (b3′),wherein Y and Y′ are as defined above, and3b-ii) when Q is Z₂, by converting the compound obtained in the step3b-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3b-iii) optionally deprotecting the compounds obtained in step 3b-i) or3b-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P³ and X₆ are asabove defined, with a compound of formula (IVg) wherein R′, y, Q are asabove defined, may be carried out 1a-i).

3c) The compounds of formula (Ig) wherein X₂ is selected from (a1′),(a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′),(m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′),wherein R^(1a) is selected from A1), A2′), A3′), A4′), R^(1a) isselected from A7), R^(2a) is selected from B7) and R^(2′) is selectedfrom B1), B2′), B3′), B4′), and R^(3a′), Y and Y′ are as above defined,T and T″ are —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, may beobtained3c-i) by reacting a compound of formula (IIIe)

P³—X₆  (IIIe)

wherein P³, X₆ are as above defined with compounds of formula (IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, Hal is an halogen atom, y is theradical Y when X₆ is selected from (a1′), (b1′), (c1′), (e1′), (f2′),(g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′),(s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆ is selectedfrom (a3′) and (b3′), wherein Y and Y′ are as defined above, and3c-ii) when Q is Z₂, by converting the compound obtained in the step3c-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3c-iii) optionally deprotecting the compounds obtained in step 3c-i) or3c-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P³ and X₆ are asabove defined, with a compound of formula (IVm) wherein y, Q, R′ are asabove defined, may be carried out as described in 1l-i)

3d) The compounds of formula (Ig) wherein X₂ is selected from (a1′),(a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′),(m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′),wherein R^(1a) is selected from A1), A2′), A3′), A4′), R^(1a) isselected from A7), R^(2a) is selected from B7) and R^(2′) is selectedfrom B1), B2′), B3′), B4′), and R^(3a′), Y and Y′ are as above defined,T and T″ are —O—CH(R′)—O—C(O)O— wherein R′ is as above defined may beobtained3d-i) by reacting a compound of formula (IIIe)

P³—X₆  (IIIe)

wherein P³ and X₆ are as above defined, with compounds of formula (IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R′ and Q are as above defined, Hal is an halogen atom y is theradical Y when X₆ is selected from (a1′), (b1′), (c1′), (e1′), (f2′),(g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′),(s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆ is selectedfrom (a3′) and (b3′), wherein Y and Y′ are as defined above, and3d-ii) when Q is Z₂, by converting the compound obtained in the step3d-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3d-iii) optionally deprotecting the compounds obtained in step 3d-i) or3d-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P³ and X₆ are asabove defined, with a compound of formula (IVo) wherein y, Q, R′ are asabove defined, may be carried out as described in 1l-i).

3e) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A5) or A6), R^(1b) is selectedfrom B5) or B6) T″ is —C(O)—, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or—O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, maybe obtained3e-i) by reacting a compound of formula (Ih)

P³⁻X₇  (Ih)

wherein P³ is as above defined and X₇ is the radical having thefollowing meaning

—HN—CH(R^(1a)—H)—C(O)-(T-Y-Q)  (a7″)

—HN—CH(R^(2a)—H)—CH₂—C(O)-(T-Y-Q)  (b7″)

wherein R^(1a) is selected from A5) or A6), R^(2a) is selected from B5)or B6), with compounds of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and3e-ii) when Q is Z₂, by converting the compound obtained in the step3e-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3e-iii) optionally deprotecting the compounds obtained in step 3e-i) or3e-ii) as above described.

The reaction of a compound of formula (Ih) wherein P³ and X₇ are asabove defined, with a compound of formula (IVa) wherein y, Q, W₁ are asabove defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-i).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3f) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A5) or A6), R^(1b) is selectedfrom B5) or B6) T″ is —C(O)—X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or—O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, maybe obtained 3f-i) by reacting a compound of formula (Ih)

P³—X₇  (Ih)

wherein P³ and X₇ are as above defined with compounds of formula (IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), X″ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and3f-ii) when Q is Z₂, by converting the compound obtained in the step3f-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3f-iii) optionally deprotecting the compounds obtained in step 3e-i) or3f-ii) as above described.

The reaction of a compound of formula (Ih) wherein P³ and X₇ are asabove defined, with a compound of formula (IVd) wherein y, Q, R_(a) areas above defined, may be carried out as described in 1-i-2).

3g) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A5), A6), R^(1b) is selected fromB5), B6), T″ is —C(O)—NR′, T is X″, NR′, —O—CH(R′)—O—C(O)— or—O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, maybe obtained3g-i) by reacting a compound of formula (Ih)

P³—X₇  (Ih)

wherein P³ and X₇ are as above defined, with compounds of formula (IVf)

R_(a)—O—C(O)—NR′-y-Q  (IVf)

wherein R_(a) and Q are as above defined, y is the radical Y′, whereinY′ is as above defined, and3g-ii) when Q is Z₂, by converting the compound obtained in the step3g-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3g-iii) optionally deprotecting the compounds obtained in step 3g-i) or3g-ii) as above described.

The reaction of a compound of formula (Ih) wherein P³ and X₇ are asabove defined, with a compound of formula (IVf) wherein y, Q, R_(a) andR′ are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P³ and X₇ are as above defined, Tis —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ii) wherein P³ and X₇ are as above defined, Tis —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3h) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A7), R^(1b) is selected from B7),T″ is —X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O—wherein X″ and R′, Y and Y′ are as above defined, may be obtained3h-i) by reacting a compound of formula (Iv)

P³—X₂  (Iv)

wherein P³ is as above defined and X₈ is the radical having thefollowing meaning

—HN—CH(R^(1a)—H)—C(O)-(T-Y-Q)  (a7″)

—HN—CH(R^(2a)—H)—CH₂—C(O)-(T-Y-Q)  (b7″)

wherein R^(1a) is selected from A7), R^(1b) is selected from B7), withcompounds of formula (IVe)

H—X″-y-Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and3h-ii) when Q is Z₂, by converting the compound obtained in the step3h-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3h-iii) optionally deprotecting the compounds obtained in step 3h-i) or3h-ii) as above described.

The reaction of a compound of formula (Iv) wherein P³ and X₈ are asabove defined, with a compound of formula (IVe) wherein y, Q, X″ are asabove defined, may be carried out as described in 1-i-1), 1-i-2) and1a-1).

The compounds of formula (Iv) wherein P³ and X₈ are as above defined, Tis —X″ are obtained as described in 3a).

The compounds of formula (Iv) wherein P³ and X₈ are as above defined, Tis —NR′ are obtained as described in 3b).

The compounds of formula (Iv) wherein P³ and X₈ are as above defined, Tis —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Iv) wherein P³ and X₈ are as above defined, Tis —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3i) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A7), R^(1b) is selected from B7),T″ is NR′, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O—wherein X″ and R′, Y and Y′ are as above defined, may be obtained3i-i) by reacting a compound of formula (Iv)

P³—X₂  (Iv)

wherein P³ and X₈ are as above defined, with compounds of formula (IVg)

H—NR′-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and3i-ii) when Q is Z₂, by converting the compound obtained in the step3i-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3i-iii) optionally deprotecting the compounds obtained in step 3i-i) or3i-ii) as above described.

The reaction of a compound of formula (Iv) wherein P³ and X₈ are asabove defined, with a compound of formula (IVg) wherein y, Q, R′ are asabove defined, may be carried out as described in 1a-i).

3l) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A7), R^(1b) is selected from B7),T″ is —O—CH(R′)—O—C(O)—, T is X″, NR′, —O—CH(R′)—O—C(O)— or—O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, maybe obtained3l-i) by reacting a compound of formula (Iv)

P³—X₈  (Iv)

wherein P³ and X₈ are as above defined with compounds of formula (IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, Hal is an halogen atom and 3l-ii) when Q is Z₂, byconverting the compound obtained in the step 3l-i) into nitro derivativeby reaction with a nitrate source as above described and3l-iii) optionally deprotecting the compounds obtained in step 3l-i) or3l-ii) as above described.

The reaction of a compound of formula (Iv) wherein P³ and X₈ are asabove defined, with a compound of formula (IVm) wherein y, Q, R′ are asabove defined, may be carried out as described in 1l-i).

3m) The compounds of formula (Ig) wherein X₂ is selected from (a7′) or(b7′) wherein R^(1a) is selected from A7), R^(1b) is selected from B7),T″ is —O—CH(R′)—O—C(O)O—, T is X″, NR′, —O—CH(R′)—O—C(O)— or—O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, maybe obtained3m-i) by reacting a compound of formula (Iv)

P³—X₂  (Iv)

m wherein P³ and X₈ are as above defined with compounds of formula (IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, Hal is an halogen atom and 3m-ii) when Q is Z₂, byconverting the compound obtained in the step 3m-i) into nitro derivativeby reaction with a nitrate source as above described and3m-iii) optionally deprotecting the compounds obtained in step 3l-i) or3m-ii) as above described.

The reaction of a compound of formula (Iv) wherein P³ and X₈ are asabove defined, with a compound of formula (IVo) wherein y, Q, R′ are asabove defined, may be carried out as described in 1l-i).

3n) The compounds of formula (Ig) wherein X₂ is selected from (a3′) or(b3′), wherein R^(1a) is selected from A5) or A6), R^(2a) is selectedfrom B5) or B6), Y′ is as above defined, T″ is C(O) may be obtained3n-i) by reacting a compound of formula (IIIf),

P³—X₉  (IIIf)

wherein P³ is as above defined, X₉ is a radical having the followingmeaning

—HN—CH(R^(1a)—H)—COOR^(3a′)  (a3″)

—HN—CH(R^(2a)—H)—CH₂COOR^(3a′)  (b3″)

wherein R^(1a) is selected from A5 or A6) and R^(2a) is selected fromB5) or B6), wherein R^(3a′) is as above defined, with compounds offormula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and3n-ii) when Q is Z₂, by converting the compound obtained in the step3n-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3n-iii) optionally deprotecting the compounds obtained in step 3n-i) or3n-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P³ and X₉ are asabove defined, with a compound of formula (IVa) wherein W₁, y, Q are asabove defined, may be carried out as described in 1-i-1), 1-i-2), 1a-1).

The compounds of formula (IIIf) wherein P³ and X₉ are as above defined,is commercially available or obtained as known in literature.

3o) The compounds of formula (Ig) wherein X₂ is selected from (a3′) or(b3′), wherein R^(1a) is selected from A5) or A6), R^(2a) is selectedfrom B5) or B6), Y′ is as above defined, T″ is C(O)—X″ wherein X″ is asabove defined, can be obtained3o-i) by reacting a compound of formula (IIIf)

P³—X₉  (IIIf)

wherein P³ and X₉ are as above defined with compounds of formula (IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), X″, Q are as above defined, y is the radical Y′, whereinY′ is as above defined, and3o-ii) when Q is Z₂, by converting the compound obtained in the step3o-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3o-iii) optionally deprotecting the compounds obtained in step 3o-i) or3o-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P³ and X₉ are asabove defined, with a compound of formula (IVd) wherein R_(a), X″, y, Qare as above defined, may be carried out as described in 1-i-2).

3p) The compounds of formula (Ig) wherein X₂ is selected from (a3′) or(b3′), wherein R^(1a) is selected from A5) or A6), R^(ea) is selectedfrom B5) or B6), Y′ is as above defined, T″ is C(O)—NR′ wherein R′ is asabove defined, can be obtained 3p-i) by reacting a compound of formula(IIIg),

P³—X₉  (IIIf)

wherein P³ and X₉ are as above defined, with compounds of formula (IVf)

R_(a)—O—(O)C—NR′-y-Q  (IVf)

wherein R_(a), R′ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and3p-ii) when Q is Z₂, by converting the compound obtained in the step3p-i) into nitro derivative by reaction with a nitrate source as abovedescribed and3p-iii) optionally deprotecting the compounds obtained in step 3p-i) or3p-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P³ and X₉ are asabove defined, with a compound of formula (IVf) wherein R_(a), R′, y, Qare as above defined, may be carried out as described in 1-i-2).

4) The compound of general formula (I) as above defined wherein a isequal to 1, the radical R_(x) is selected from (d1), (d2), (d3), (d4),(d7), (d8), Z is C(O), can be obtained 4-i) by reacting a compound offormula (IIb)

R—C(O)—O—R_(a)  (IIb)

wherein R and R_(a) are as above defined, with a compound of formula(Im)

H—X₁₂  (Im)

wherein X₁₂ is the radical R_(x) having the following meaning

—HN—CH(R^(12′))—CH₂—O-(T′″-Y-Q)  (d1′)

—O—CH₂—CH(R^(12′))—NH-(T′-Y-Q)  (d2′)

—HN—CH(R^(12a)-T″-Y′-Q)-CH₂OH  (d3′)

—O—CH₂—CH(R^(12a)-T′″-Y′-Q)-NHR^(4a)  (d4′)

—HN—CH(R^(12a-)T″-Y′-Q)-CH₂—O-(T′″-Y-Q)  (d7′)

—O—CH₂—CH(R^(12a)-T′″-Y′-Q)-NH-(T′-Y-Q)  (d8′)

wherein R^(12′) is

D1),

D2′) —CH₂—OP¹, —CH(CH₃)—OP¹, —CH₂[(C₆H₄)-4-OP¹],—CH₂-[(C₆H₃)-(3,5-diiodo)-4-OP¹], —CH₂-[(C₆H₃)-3-nitro-4-OP¹];D3′) —CH₂—NHR″″, —(CH₂)₂—NHR″″, —(CH₂)₃—NHR″″, —(CH₂)₄—NHR″″, whereinR″″ is as above defined;D4′) —CH₂—C(O)R′″″, —(CH₂)₂—C(O)R″″, —(CH₂)₄—C(O)R″″, wherein R′″″ is asabove defined;wherein R^(12a) is as above defined;and4-ii) when Q is Z₂, by converting the compound obtained in the step 4-i)into nitro derivative by reaction with a nitrate source as abovedescribed and4-iii) optionally deprotecting the compounds obtained in step 4-i) or4-ii) as above described.

The reaction of a compound of formula (IIb) wherein R and R_(a) are asabove defined, with a compound of formula (Im) wherein X₁₂ is as abovedefined, may be carried out as described in 1-i-2).

4a) The compound of formula (Im) wherein X₁₂ is selected from (d1′),(d2′), (d3′) or (d4′) wherein R^(12′) is selected from D1), D2′), D3′)or D4′) and R^(12a) is selected from D5) or D6), Y and Y′ are as abovedefined, T′ and T″ and T′″ are C(O) can be obtained4a-i) by reacting a compound of formula (IIIi),

P⁴—X₁₃  (IIIi)

wherein P⁴ is P³ or P¹ as above defined and X₁₃ is a radical having thefollowing meaning

—HN—CH(R^(12′))—CH₂—OH  (d1″)

—O—CH₂—CH(R^(12′))—NH₂  (d2″)

—HN—CH(R^(12a)—H)—CH₂OP¹  (d3″)

—O—CH₂—CH(R^(12a)—H)—NHR^(4a′)  (d4″)

wherein R^(12′) is D1), D2′), D3′) or D4′), R^(12a) is D5) or D6),R^(4a′) and P¹ are as above defined, with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein Q and W₁ are as above defined, y is the radical Y when X₁₃ isselected from (d1′) or (d2′), y is the radical Y′ when X₁₃ is selectedfrom (d3′) or (d4′), wherein Y and Y′ are as above defined, and4a-ii) when Q is Z₂, by converting the compound obtained in the step4a-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4a-iii) optionally deprotecting the compounds obtained in step 4a-i) or4a-ii) as above described.

The reaction of a compound of formula (IIIi) wherein X₁₃ and P⁴ are asabove defined, with a compound of formula (IVa) wherein W₁, y and Q areas above defined, may be carried out as described in 1-i-1) and 1-i-2).

The compounds of formula (IIIi) wherein X₁₃ and P⁴ are as abovedescribed, are commercially available or known in literature.

4b) The compound of formula (Im) wherein X₁₂ is selected from (d1′),(d2′), (d3′) or (d4′) wherein R^(12′) is selected from D1), D2′), D3′)or D4′) and R^(12a) is selected from D5) or D6), Y and Y′ are as abovedefined, T′ and T″ and T′″ are C(O)—X″, wherein X″ is as above defined,can be obtained4b-i) by reacting a compound of formula (IIIi),

P⁴—X₁₃  (IIIi)

wherein P⁴ and X₁₃ are defined above, with a compound of formula (IVd)

R_(a)—O—(O)C—X″-y-Q  (IVd)

wherein Q, R_(a) and X″ are as above defined, y is the radical Y whenX₁₃ is selected from (d1′) or (d2′), y is the radical Y's when X₁₃ isselected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and4b-ii) when Q is Z₂, by converting the compound obtained in the step4b-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4b-iii) optionally deprotecting the compounds obtained in step 4b-i) or4b-ii) as above described.

The reaction of a compound of formula (IIIi) wherein X₁₃ and P⁴ are asabove defined, with a compound of formula (IVd) wherein y, Q, R_(a) andX″ are as above defined, may be carried out as described in 1-i-2).

4c) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D5) or D6), Y′ and Y are as abovedefined, T′ and T″ and T′″ are C(O), can be obtained4c-i) by reacting a compound of formula (IIIl),

P⁴—X₁₄  (IIIl)

wherein P⁴ is P¹ or P³, X₁₄ is the radical having the following meaning

—HN—CH(R^(12a)—H)—CH₂—OH  (d7″)

—O—CH₂—CH(R^(12a)—H)—NH₂  (d8″)

wherein R^(12a) is selected from D5) or D6), with a compound of formula(IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and4c-ii) when Q is Z₂, by converting the compound obtained in the step4c-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4c-iii) optionally deprotecting the compounds obtained in step 4c-i) or4c-ii) as above described.

The reaction of a compound of formula (IIIl) wherein P⁴ and X₁₄ are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y andQ are as above defined, may be carried out as described in 1-i-1) usinga ratio (IIIl)/(IVa) 1:2.

The reaction of a compound of formula (IIIl) wherein P⁴ and X₁₄ are asabove defined, with a compound of formula (IVa) wherein W₁ is OR_(a), yand Q are as above defined, may be carried out as described in 1-i-2)using a ratio (IIIl)/(IVa) 1:2.

The compounds of formula (IIIl) wherein P⁴ and X₁₄ are as abovedescribed, are commercially available or known in literature.

4d) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D5) or D6), Q, Y and Y′ are asabove defined, T′, T′″ and T″ are C(O), can be obtained4d-i) by reacting a compound of formula (In)

P⁴—X₁₅  (In)

wherein P⁴ is defined above and X₁₅ is the radical having the followingmeaning

—HN—CH(R^(12a)—H)—CH₂—O-(T′″-Y-Q)  (d7′″)

—O—CH₂—CH(R^(12a)—H)—NH-(T′-Y-Q)  (d8′″)

wherein R^(12a) is selected from D5) or D6), Y, Q, T′ and T′″ are asabove defined, with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁, y and Q′ are as above defined, y is the radical Y′, whereinY′ is as above defined, and4d-ii) when Q is Z₂, by converting the compound obtained in the step4d-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4d-iii) optionally deprotecting the compounds obtained in step 4d-i) or4d-ii) as above described.

The reaction of a compound of formula (In) wherein P⁴ and X₁₅ are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y andQ are as above defined, may be carried out as described in 1-i-1).

The reaction of a compound of formula (In) wherein P⁴ and X₁₅ are asabove defined, with a compound of formula (IVa) wherein W₁ is OR_(a), yand Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein P⁴ and X₁₅ are as above defined,T′ and T′″ are —C(O)— can by obtained as described in 4a).

4e) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D5) or D6), Q, Y and Y′ are asabove defined, T″ is C(O)—X″ wherein X″ is as above defined, T′ and T′″are C(O), can be obtained4e-i) by reacting a compound of formula (In)

P⁴X₁₅  (In)

wherein P⁴ and X₁₅ are defined above, with a compound of formula (IVa)

W₁—(O)C-y-Q  (IVa)

wherein W₁, y and Q are as above defined, y is the radical Y′, whereinY′ is as above defined, and4e-ii) when Q is Z₂, by converting the compound obtained in the step1e-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4e-iii) optionally deprotecting the compounds obtained in step 4e-i) or4e-ii) as above described.

The reaction of a compound of formula (In) wherein P⁴ and X₁₅ are asabove defined, with a compound of formula (IVa) wherein W₁ is OH, y andQ are as above defined, can by carried out as described in 1-i-1).

The reaction of a compound of formula (In) wherein P⁴ and X₁₅ are asabove defined, with a compound of formula (IVa) wherein W₁ is OR_(a), yand Q are as above defined, can by carried out as described in 1-i-2).

The compounds of formula (In) wherein P⁴ and X₁₅ are as above definedcan by obtained as described in 4b).

4f) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D5) or D6), Y and Y′ are the sameand are as above defined, T′, T″ and T′″ are C(O)—X″ wherein X″ is asabove defined, can be obtained4f-i) by reacting a compound of formula (IIIl),

P⁴—X₁₄  (IIIl)

wherein P⁴ and X₁₄ are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), X″ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and4f-ii) when Q is Z₂, by converting the compound obtained in the step4f-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4f-iii) optionally deprotecting the compounds obtained in step 4f-i) or4f-ii) as above described.

The reaction of a compound of formula (IIIl) wherein P⁴ and X₁₄ are asabove defined, with a compound of formula (IVd) wherein R_(a), X″, y andQ are as above defined, may be carried out as described in 1-i-2) usinga ratio (IIIl)/(IVd) 1:2.

4g) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D5) or D6), Q, Y and Y′ are asabove defined, T″ is C(O)—X″, T′ and T′″ are C(O) or C(O)—X″, wherein X″is as above defined, can be obtained4g-i) by reacting a compound of formula (In)

P⁴X₁₅  (In)

wherein P⁴ and X₁₅ are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), X″ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and4g-ii) when Q is Z₂, by converting the compound obtained in the step4g-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4g-iii) optionally deprotecting the compounds obtained in step 4g-i) or4g-ii) as above described.

The reaction of a compound of formula (In) wherein P⁴ and X₁₅ are asabove defined, with a compound of formula (IVd) wherein R_(a), X″, y andQ are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein T′ or T′″ are C(O), P⁴ and X₁₅ areas above defined are obtained as described in 4a-i), 4a-ii).

The compounds of formula (In) wherein T′ or T′″ are C(O)—X″, wherein P⁴and X₁₅ are as above defined are obtained as described in 4b-i), 4b-ii).

4h) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12′) is selected from D5) or D6), Q, Y and Y′ are asabove defined, T″ is C(O)—NR′—, T′ and T′″ are C(O) or C(O)—X″, whereinX″ is as above defined, can be obtained4h-i) by reacting a compound of formula (In)

P⁴—X₁₅  (In)

wherein P⁴ and X₁₅ are as above defined, with a compound of formula

R_(a)—O—(O)C—NR′-y-Q  (IVf)

wherein R_(a), R′ and Q are as above defined, y is the radical Y′,wherein Y′ is as above defined, and4h-ii) when Q is Z₂, by converting the compound obtained in the step4h-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4h-iii) optionally deprotecting the compounds obtained in step 4h-i) or4h-ii) as above described.

The reaction of a compound of formula (In) P⁴ and X₁₅ are as abovedefined, with a compound of formula (IVf) wherein R_(a), R′, y, Q are asabove defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein T′ or T′″ are C(O), wherein P⁴ andX₁₅ are as above defined, are obtained as described in 4a-i), 4a-ii).

The compounds of formula (In) wherein T′ or T′″ are C(O)—X″, wherein P⁴and X₁₅ are as above defined, are obtained as described in 4b-i),4b-ii).

4i) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D7), Q, Y and Y′ are as abovedefined, T″ is X″, wherein X″ is as above defined, T′ and T′″ are C(O)or C(O)—X″, wherein X″ is as above defined, can be obtained4i-i) by reacting a compound of formula (Ir),

P⁴—X₁₆  (Ir)

—HN—CH(R^(12a)—OH)—CH₂—O-(T′″-Y-Q)  (d7″″)

—O—CH₂—CH(R^(12a)—OH)—NH-(T′-Y-Q)  (d8″″)

wherein P⁴ is as above defined, R^(12a) is selected from D7), with acompound of formula (IVe)

HX″-y-Q  (IVe)

wherein Y′, X″ and Q are as above defined, y is the radical Y′, whereinY′ is as above defined, and4i-ii) when Q is Z₂, by converting the compound obtained in the step4i-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4i-iii) optionally deprotecting the compounds obtained in step 4i-i) or4i-ii) as above described.

The reaction of a compound of formula (Ir) wherein P⁴ and X₁₆ are asabove defined with a compound of formula (IVe) wherein y, X″ and Q areas above defined, may be carried out as described in 1-i-1).

The compounds of formula (Ir) wherein T′ or T′″ are C(O), P⁴ and X₁₆ areas above defined are obtained as described in 4a-i), 4a-ii).

The compounds of formula (Ir) wherein T′ or T′″ are C(O)—X″, P⁴ and X₁₆are as above defined, are obtained as described in 4b-i), 4b-ii).

41) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12a) is selected from D7), Q, Y and Y′ are as abovedefined, T″ is —NR′ wherein R′ is as above defined, T′ and T′″ are C(O)or C(O)—X″, wherein X″ is as above defined, can be obtained

4l-i) by reacting a compound of formula (Ir),

P⁴—X₁₆  (Ir)

wherein P⁴ and X₁₆ are as above defined and R^(12a) is selected fromD7), with a compound of formula

HR′N-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and4l-ii) when Q is Z₂, by converting the compound obtained in the step4l-i) into nitro derivative by reaction with a nitrate source such abovedescribed and4l-iii) optionally deprotecting the compounds obtained in step 4l-i) or4l-ii) as above described.

The reaction of a compound of formula (Ir) P⁴ and X₁₆ are as abovedefined, with a compound of formula (IVg) wherein R′, y, Q are as abovedefined, may be carried out as described in 1-i-4m) The compound offormula (Im) wherein X₁₂ is selected from (d7′) or (d8′) wherein R^(12′)is selected from D7), Q, Y and Y′ are as above defined, T″ is—O—CH(R′)—O—C(O)—, wherein R′ is as above defined, T′ and T′″ are C(O)or C(O)—X″, wherein X″ is as above defined, can be obtained

4m-i) by reacting a compound of formula (Ir),

P⁴—X₁₆  (Ir)

wherein P⁴ and X₁₆ are as above defined and R^(12a) is selected fromD7), with a compound of formula (IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, Hal is an halogen atom, y is theradical Y′, wherein Y′ is as above defined, and4m-ii) when Q is Z₂, by converting the compound obtained in the step4m-i) into nitro derivative by reaction with a nitrate source such abovedescribed and4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or1m-ii) as above described.

The reaction of a compound of formula (Ir) wherein P⁴ and X₁₆ are asabove defined, with a compound of formula (IVm) wherein y, Q, R′ are asabove defined, may be carried out as described in 1l-i).

4n) The compound of formula (Im) wherein X₁₂ is selected from (d7′) or(d8′) wherein R^(12′) is selected from D7), Q, Y and Y′ are as abovedefined, T″ is —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, T′and T′″ are C(O) or C(O)—X″, wherein X″ is as above defined, can beobtained4n-i) by reacting a compound of formula (Ir),

P⁴—X₁₆  (Ir)

wherein P⁴ and X₁₆ are as above defined and R^(12′) is selected fromD7), with a compounds of formula (IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R and Q′ are as above defined, Hal is an halogen atom, y is theradical Y′, wherein Y′ is as above defined, and 4n-ii) when Q is Z₂, byconverting the compound obtained in the step 4n-i) into nitro derivativeby reaction with a nitrate source as above described and4n-iii) optionally deprotecting the compounds obtained in step 4n-i) or4n-ii) as above described.

The reaction of a compound of formula (Ir) wherein P⁴ and X₁₆ are asabove defined, with a compound of formula (IVo) wherein y, R′, Q, Halare as above defined, may be carried out as described in 1l-i).

4o) The compound of formula (Im) wherein X₁₂ is (selected from d3′) or(d4′) wherein R^(12a) is selected from D7), Y′ is as above defined, T″is X″, wherein X″ is defined above, can be obtained4o-i) by reacting a compound of formula (IIIm),

P⁴X₁₇  (IIIm)

wherein P⁴ is defined above and X₁₇ is the radical

—HN—CH(R^(12a)—H)—CH₂OP¹  (d3″)

—O—CH₂—CH(R^(12a)—H)—NHR^(4a′)  (d4″)

wherein R^(12a) is selected from D7), wherein P¹ and R^(4a′) are asabove defined, with a compound of formula (IVe)

HX″-y-Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and4o-ii) when Q is Z₂, by converting the compound obtained in the step4o-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4o-iii) optionally deprotecting the compounds obtained in step 4o-i) or4o-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P⁴ and X₁₇ are asabove defined with a compound of formula (IVe) wherein y, X″ and Q areas above defined, may be carried out as described in 1-i-1).

The compounds of formula (IIIm), wherein P⁴ and X₁₇ are as abovedefined, are commercially available or obtained as known in literature.

4p) The compound of formula (Im) wherein X₁₂ is selected from (d3′) or(d4′) wherein R^(12a) is selected from D7), Y′ is as above defined, T″is —NR′ wherein R′ is as above defined, can be obtained4p-i) by reacting a compound of formula (IIIm),

P⁴—X₁₇  (IIIm)

wherein P⁴ and X₁₇ are as defined above, wherein R^(12a) is selectedfrom D7), with a compound of formula

HR′N-y-Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and4p-ii) when Q is Z₂, by converting the compound obtained in the step4p-i) into nitro derivative by reaction with a nitrate source such abovedescribed and4p-iii) optionally deprotecting the compounds obtained in step 4p-i) or4p-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P⁴ and X₁₇ are asabove defined, with a compound of formula (IVg) wherein R′, y, Q are asabove defined, may be carried out as described in 1a-i).

4q) The compound of formula (Im) wherein X₁₂ is selected from (d3′) or(d4′) wherein R^(12a) is selected from D7), Y′ is as above defined, T″is —O—CH(R′)—O—C(O)— wherein R′ is as above defined, can be obtained4q-i) by reacting a compound of formula (IIIm),

P⁴—X₁₇  (IIIm)

wherein P⁴ and X₁₇ are as defined above, wherein R^(12a) is selectedfrom D7), with a compound of formula (IVm)

Hal-CH(R′)—O—(O)C-y-Q  (IVm)

wherein R′ and Q are as above defined, Hal is an halogen atom, y is theradical Y′, wherein Y′ is as above defined, and 4q-ii) when Q is Z₂, byconverting the compound obtained in the step 4q-i) into nitro derivativeby reaction with a nitrate source such above described and4q-iii) optionally deprotecting the compounds obtained in step 4q-i) or4q-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P⁴ and X₁₇ are asabove defined, with a compound of formula (IVm) wherein R′, y, Q are asabove defined, may be carried out as described in 1l-i).

4r) The compound of formula (Im) wherein X₁₂ is selected from (d3′) or(d4′) wherein R^(12a) is selected from D7), Y′ is as above defined, T″is —O—CH(R′)—O—C(O)—O— wherein R′ is as above defined, can be obtained4r-i) by reacting a compound of formula (IIIm),

P⁴—X₁₇  (IIIm)

wherein P⁴ and X₁₇ are as defined above, wherein R^(12a) is selectedfrom D7), with a compound of formula (IVo)

Hal-CH(R′)—O—(O)C—O-y-Q  (IVo)

wherein R′ and Q are as above defined, Hal is an halogen atom, y is theradical Y′, wherein Y′ is as above defined, and4r-ii) when Q is Z₂, by converting the compound obtained in the step4r-i) into nitro derivative by reaction with a nitrate source as abovedescribed and4r-iii) optionally deprotecting the compounds obtained in step 4r-i) or4r-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P⁴ and X₁₇ are asabove defined, with a compound of formula (IVo) wherein y, R′, Q, Halare as above defined, may be carried out as described in 1l-i).

5) The compound of general formula (I) as above defined wherein a isequal to 0, R_(x) is a radical selected from (d5), (d6), (d9) or (d10),wherein R^(12b) is selected from D10) can be obtained5-i) by reacting a compound of formula (IIa)

R—H  (IIa)

wherein R is as above defined, with a compound of formula (Is)

W—X₁₈  (Is)

wherein W is as above defined, X₁₈ is the radical having the followingmeanings

—R^(12b)—CH(NHR^(4a))—CH₂—O-(T′″-Y-Q)  (d5′)

—R^(12b)—CH(CH₂OH)—NH-(T′-Y-Q)  (d6′)

—R^(12b)—CH(NH-T′″-Y′-Q)-CH₂—O-(T′-Y-Q)  (d9′)

—R^(12b)—CH(CH₂—O-T′″-Y′-Q)-NH-(T′-Y-Q)  (d10′)

wherein R^(12b) is selected from D10), T′, T′″, Y, Y′ and Q are as abovedefined and5-ii) when Q is Z₂, by converting the compound obtained in the step 5-i)into nitro derivative by reaction with a nitrate source as abovedescribed and5-iii) optionally deprotecting the compounds obtained in step 5-i) or5-ii) as above described.

The reaction of a compound of formula (IIa) wherein R is as abovedefined, with a compound of formula (Is) wherein W and X₁₈ are as abovedefined may be carried out as described in 1).

5a) The compounds of formula (Is) wherein X₁₈ is a radical of formula(d5′) or (d6′), wherein R^(12b) is selected from D10), T′ and T′″ areC(O) can be obtained5a-i) by reacting a compound of formula (IIIn),

P²—X₁₉  (IIIn)

wherein P² is as above defined, X₁₉ is the radical having the followingmeanings

—R^(12b)—CH(NHP³)—CH₂—OH  (d5″)

—R^(12b)—CH(CH₂OP¹)—NH₂  (d6″)

wherein P¹ and P³ are as above defined and R^(12b) is selected fromD10), with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁, y, Q are as above defined, y is the radical Y, wherein Y isas above defined, and5a-ii) when Q is Z₂, by converting the compound obtained in the step5a-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5a-iii) optionally deprotecting the compounds obtained in step 5a-i) or5a-ii) as above described.

The reaction of a compound of formula (IIIn) wherein P² and X₁₉ are asabove defined, with a compound of formula (IVa) W₁, y, and Q are asabove defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

The compounds of formula (IIIn), wherein P² and X₁₉ are as abovedefined, are commercially available or obtained as known in literature.

5b) The compounds of formula (Is) wherein X₁₈ is a radical of formula(d5′) or (d6′), wherein R^(12b) is selected from D10), T′ and T′″ areC(O)—X″, wherein X″ is defined above, can be obtained5b-i) by reacting a compound of formula (IIIn),

P²—X₁₉  (IIIn)

wherein P² and X₁₉ are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and Q, X″ are as above defined, y is the radical Y,wherein Y is as above defined, and5b-ii) when Q is Z₂, by converting the compound obtained in the step5b-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5b-iii) optionally deprotecting the compounds obtained in step 5b-i) or5b-ii) as above described.

The reaction of a compound of formula (IIIn) wherein P² and X₁₉ are asabove defined, with a compound of formula (IVd) R_(a), y, Q, X″ are asabove defined may be carried out as described in 1-i-2).

5c) The compounds of formula (Is) wherein X₁₈ is a radical of formula(d9′), wherein R^(12b) is selected from D10), Y and Y′ are as definedabove, T′ is C(O)— and T′″ is C(O) or C(O)—X″, wherein X″ is definedabove, can be obtained5c-i) by reacting a compound of formula (It),

P²—X₂₀  (It)

wherein P² is as above defined and X₂₀ is the radical having thefollowing meanings

—R^(12b)—CH(NH₂)—CH₂—O-(T′″-Y-Q)  (d9″)

wherein R^(12b) is selected from D10), T′″, Y and Q are as abovedefined, with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and5c-ii) when Q is Z₂, by converting the compound obtained in the step5c-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5c-iii) optionally deprotecting the compounds obtained in step 5c-i) or5c-ii) as above described.

The reaction of a compound of formula (It) wherein P² and X₂₀ are asabove defined, with a compound of formula (IVa) wherein W₁, y, Q are asabove defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

5d) The compounds of formula (Is) wherein X₁₈ is a radical of formula(d9′), wherein R^(12b) is selected from D10), T′ is C(O)—X″ and T′″ isC(O)— or C(O)—X″, wherein X″ is defined above, can be obtained5d-i) by reacting a compound of formula (It′),

P²—X_(20′)  (It′)

wherein P² and X_(20′) are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and Q, X″ are as above defined, y is the radical Y′,wherein Y′ is as above defined, and5d-ii) when Q is Z₂, by converting the compound obtained in the step5d-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5d-iii) optionally deprotecting the compounds obtained in step 5d-i) or5d-ii) as above described.

The reaction of a compound of formula (It′) wherein P² and X_(20′) areas above defined, with a compound of formula (IVd) R_(a), y, Q, X″ areas above defined may be carried out as described in 1-i-2).

5e) The compounds of formula (Is) wherein X₁₈ is the radical of formula(d10′), wherein R^(12b) is selected from D10), Y and Y′ are as definedabove, T′″ is C(O)— and T′ is C(O) or C(O)—X″, wherein X″ is definedabove, can be obtained5e-i) by reacting a compound of formula (It),

P²—X₂₀  (It)

wherein P² is as above defined and X₂₀ is the radical having thefollowing meaning

—R^(12b)—CH(CH₂—OH)—NH-(T′-Y-Q)  (d10″)

wherein R^(12b) is selected from D10), T′, Y and Q are as above defined,with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and5e-ii) when Q is Z₂, by converting the compound obtained in the step5e-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5e-iii) optionally deprotecting the compounds obtained in step 5e-i) or5e-ii) as above described.

The reaction of a compound of formula (It) wherein P² and X₂₀ are asabove defined, with a compound of formula (IVa) wherein W₁, y, Q are asabove defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

5f) The compounds of formula (Is) wherein X₁₈ is the radical of formula(d10′), wherein R^(12b) is selected from D10), T′″ is C(O)—X″ and T′ isC(O)— or C(O)—X″, wherein X″ is defined above, can be obtained5f-i) by reacting a compound of formula (It′),

P²—X₂₀  (It′)

wherein P² and X_(20′) are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and Q, X″ are as above defined, y is the radical Y′,wherein Y′ is as above defined, and5f-ii) when Q is Z₂, by converting the compound obtained in the step5f-i) into nitro derivative by reaction with a nitrate source as abovedescribed and5f-iii) optionally deprotecting the compounds obtained in step 5f-i) or5f-ii) as above described.

The reaction of a compound of formula (It′) wherein P² and X_(20′) areas above defined, with a compound of formula (IVd) R_(a), y, Q, X″ areas above defined may be carried out as described in 1-i-2).

6) The compounds of general formula (I) as above defined wherein a isequal to 1, R_(x) is a radical selected from (d5), (d6), (d9) or (d10),wherein R^(12b) is selected from D10), Z is —CH(R′)—O—, wherein R′ isdefined above, can be obtained6-i) by reacting a compound of formula (IIa)

R—OH  (IIa)

wherein R is as above defined with a compound of formula (Iu)

Hal-CH(R′)—O—X₂₁  (Iu)

wherein Hal is an halogen atom, R′ is as above defined and X₂₁ is aradical selected from (d5′), (d6′), (d9′) or (d10′), wherein R^(12b) isselected from D10), and6-ii) when Q is Z₂, by converting the compound obtained in the step 6-i)into nitro derivative by reaction with a nitrate source as abovedescribed and6-iii) optionally deprotecting the compounds obtained in step 6-i) or6-ii) as above described.

The reaction of a compound of formula (Iu) wherein Hal, X₂₁ and R′ areas above defined, with a compound of formula (IIa) wherein R is as abovedefined, may be carried out as described in 1l-i).

The compounds of formula (Iu) are obtained by reacting a compoundR′—CHO, wherein R′ is as above defined with compounds of formula (IIIo)

W—X₂₂  (IIIo)

wherein W is a chlorine atom, X₂₂ is the radical having the followingmeanings

—R^(12b)—CH(NHP³)—CH₂—O-(T′″-Y-Q)  (d5′″)

—R^(12b)—CH(CH₂OP¹-—H-(T′-Y-Q)  (d6′″)

R^(12b)—CH(NH-T′-Y′-Q)-CH₂—O-(T′″-Y-Q)  (d9′″)

—R^(12b)—CH(CH₂—O-T′″-Y′-Q)-NH-(T′-Y-Q)  (d10′″)

wherein R^(12b), P³, P¹, T′, T″, Y′, Y and Q are as above defined, andZnCl₂ as known in literature.

The compounds of formula (IIIo), wherein W and X₂₂ are as above defined,may be carried out as described in 5).

7) The compounds of general formula (I) as above defined wherein a isequal to 1, R_(x) is a radical selected from (d5), (d6), (d9) or (d10),wherein R^(12b) is selected from D8) or D9), Z is —C(O)—, can beobtained7-i) by reacting a compound of formula (IIb)

R—C(O)—O—R_(a)  (IIb)

wherein R and R_(a) are as above defined with a compound of formula (Iv)

H—X₂₃  (Iv)

wherein X₂₃ is a radical selected from (d5′), (d6′), (d9′) or (d10′),wherein R^(12b) is selected from D8) or D9), and7-ii) when Q is Z₂, by converting the compound obtained in the step 7-i)into nitro derivative by reaction with a nitrate source as abovedescribed and7-iii) optionally deprotecting the compounds obtained in step 7-i) or7-ii) as above described.

The reaction of a compound of formula (Iv) wherein X₂₃ and is as abovedefined, with a compound of formula (IIb) wherein R is as above defined,may be carried out as described in 1l-i).

8) The compound of general formula (I) as above defined wherein a isequal to 0, R_(x) is a radical selected from (a5), (a6), (a9) or (a10),(b5), (b6), (b9) or (b10) wherein R^(1b) is selected from A10) andR^(2b) is selected from B10), can be obtained8-i) by reacting a compound of formula (IIa)

R—H  (IIa)

wherein R is as above defined, with a compound of formula (Iz)

W—X₂₄  (Iz)

wherein W is as above defined, X₂₄ is the radical R_(x) having thefollowing meanings

—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y-Q)  (a5′)

—R^(1b)—CH(COOR^(2a))NH-(T′-Y-Q)  (a6′)

—R^(1b)—CH(NH-T′-Y′-Q)-C(O)-(T-Y-Q)  (a9′)

—R^(1b)—CH(C(O)-T′-Y′-Q)-NH-(T-Y-Q)  (a10′)

—R^(2b)—CH(NHR^(4a))—CH₂C(O)-(T-Y-Q)  (b5′)

—R^(2b)—CH(CH₂COOR^(3a))NH-(T′-Y-Q)  (b6′)

—R^(2b)—CH(NH-T′-Y′-Q)-CH₂C(O)-(T-Y-Q)  (b9′)

—R^(2b)—CH(CH₂C(O)-T′-Y′-Q)-NH-(T-Y-Q)  (b10′)

wherein R^(1b) is selected from A10), R^(2b) is selected from B10), T,T′, Y and Q are as above defined and8-ii) when Q is Z₂, by converting the compound obtained in the step 8-i)into nitro derivative by reaction with a nitrate source as abovedescribed and8-iii) optionally deprotecting the compounds obtained in step 8-i) or8-ii) as above described.

The reaction of a compound of formula (IIa) wherein R is as abovedefined, with a compound of formula (Iv) wherein W and X₂₄ are as abovedefined may be carried out as described in 1).

8a) The compounds of formula (Iz) wherein X₂₄ is a radical of formula(a5′), (a6′), (b5′) or (b6′), wherein R^(1b) is selected from A10) andR^(2b) is selected from B10), T and T′ are C(O) can be obtained8a-i) by reacting a compound of formula (IIIq),

P²—X₂₅  (IIIq)

wherein P² is as above defined, X₂₅ is the radical having the followingmeanings

—R^(1b)—CH(NHP³-C(O)—OH  (a5″)

—R^(1b)—CH(COOP²—NH₂  (a6″)

—R^(2b)—CH(NHP³)—CH₂C(O)—OH  (b5″)

—R^(2b)—CH(CH₂COOP²)NH₂  (b6″)

wherein P² and P³ are as above defined and R^(1b) is selected from A10),R^(2b) is selected from B10), with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y, wherein Y isas above defined, and8a-ii) when Q is Z₂, by converting the compound obtained in the step8a-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8a-iii) optionally deprotecting the compounds obtained in step 8a-i) or8a-ii) as above described.

The reaction of a compound of formula (IIIq) wherein P² and X₂₅ are asabove defined, with a compound of formula (IVa) W₁, Y, and Q are asabove defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

The compounds of formula (IIIq), wherein P² and X₂₅ are as abovedefined, are commercially available or obtained as known in literature.

8b) The compounds of formula (Iz) wherein X₂₄ is the radical of formula(a5′), (a6′), (b5′) or (b6′), wherein R^(1b) is selected from A10) andR^(2b) is selected from B10), T and T′ are C(O)—X″, wherein X″ isdefined above, can be obtained

8b-i) by reacting a compound of formula (IIIq),

P²—X₂₅  (IIIq)

wherein P² and X₂₅ are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a), Q and X″ are as above defined, y is the radical Y,wherein Y is as above defined, and8b-ii) when Q is Z₂, by converting the compound obtained in the step8b-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8b-iii) optionally deprotecting the compounds obtained in step 8b-i) or8b-ii) as above described.

The reaction of a compound of formula (IIIq) wherein P² and X₂₅ are asabove defined, with a compound of formula (IVd) R_(a), y, Q, X″ are asabove defined may be carried out as described in 1-i-2).

8c) The compounds of formula (Iz) wherein X₂₄ is the radical of formula(a9′) or (b9′) wherein R^(1b) is selected from A10), and R^(2b) isselected from B10) Y and Y′ are as defined above, T is C(O)— or C(O)—X″,wherein X″ is defined above and T′ is C(O) can be obtained8c-i) by reacting a compound of formula (Iy),

P²—X₂₆  (Iy)

wherein P² is as above defined and X₂₆ is the radical having thefollowing meanings

—R^(1b)—CH(NH₂—C(O)-(T-Y-Q)  (a9″)

—R^(2b)—CH(NH₂—CH₂C(O)-(T-Y-Q)  (b9″)

wherein R^(1b) is selected from A10) and R^(2b) is selected from B10),with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and8c-ii) when Q is Z₂, by converting the compound obtained in the step8c-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8c-iii) optionally deprotecting the compounds obtained in step 8c-i) or8c-ii) as above described.

The reaction of a compound of formula (Iy) wherein P² and X₂₆ are asabove defined, with a compound of formula (IVa) wherein W₁, y, Q are asabove defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

8d) The compounds of formula (Iz) wherein X₂₄ is the radical of formula(a9′) or (b9′) wherein R^(1b) is selected from A10), R^(2b) is selectedfrom B10), Y and Y′ are as defined above, T is C(O)— or C(O)—X″, whereinX″ is defined above and T′ is C(O)—X″ can be obtained8d-i) by reacting a compound of formula (Iy),

P²—X₂₆  (Iy)

wherein P² and X₂₆ are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and X″ are as above defined, y is the radical Y′, whereinY′ is as above defined, and8d-ii) when Q is Z₂, by converting the compound obtained in the step8d-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8d-iii) optionally deprotecting the compounds obtained in step 8d-i) or8d-ii) as above described.

The reaction of a compound of formula (Iy) wherein P² and X₂₀ are asabove defined, with a compound of formula (IVd) R_(a), y, Q, X″ are asabove defined may be carried out as described in 1-i-2).

8e) The compounds of formula (Iz) wherein X₂₄ is the radical of formula(a10′) or (b10′) wherein R^(1b) is selected from A10), and R^(2b) isselected from in B10) Y and Y′ are as defined above, T is C(O)— orC(O)—X″, wherein X″ is defined above and T′ is C(O) can be obtained8e-i) by reacting a compound of formula (Iy′),

P²—X₂₆  (Iy′)

wherein P² is as above defined and X_(26′) is the radical having thefollowing meanings

—R^(1b)—CH(C(O)—OH)—NH-(T-Y-Q)  (a10″)

—R^(2b)—CH(CH₂C(O)—OH)—NH-(T-Y-Q)  (b10″)

wherein R^(1b) is selected from selected from A10) and R^(2b) is B10),with a compound of formula (IVa)

W₁—C(O)—Y-Q  (IVa)

wherein W₁ and Q are as above defined, y is the radical Y′, wherein Y′is as above defined, and8e-ii) when Q is Z₂, by converting the compound obtained in the step8e-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8e-iii) optionally deprotecting the compounds obtained in step 8e-i) or8e-ii) as above described.

The reaction of a compound of formula (Iy′) wherein P² and X₂₆, are asabove defined, with a compound of formula (IVa) wherein W₁, y, Q are asabove defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3)and 1a-1).

8f) The compounds of formula (Iz) wherein X₂₄ is the radical of formula(a10′) or (b10′) wherein R^(1b) is selected from A10), and R^(2b) isselected from B10), Y and Y′ are as defined above, T is C(O)— orC(O)—X″, wherein X″ is defined above and T′ is C(O)—X″ can be obtained8f-i) by reacting a compound of formula (Iy′),

P²—X_(26′)  (Iy′)

wherein P² and X_(26′) are as above defined, with a compound of formula(IVd)

R_(a)—O—C(O)—X″-y-Q  (IVd)

wherein R_(a) and X″ are as above defined, y is the radical Y′, whereinY′ is as above defined, and8f-ii) when Q is Z₂, by converting the compound obtained in the step8f-i) into nitro derivative by reaction with a nitrate source as abovedescribed and8f-iii) optionally deprotecting the compounds obtained in step 8f-i) or8f-ii) as above described.

The reaction of a compound of formula (Iy′) wherein P² and X_(26′) areas above defined, with a compound of formula (IVd) R_(a), y, Q, X″ areas above defined may be carried out as described in 1-i-2).

9) The compounds of general formula (I) as above defined wherein a isequal to 1, R_(x) is a radical selected from (a5), (a6), (a9) or (a10),(b5), (b6), (b9) or (b10) wherein R^(1b) is selected from A8) or A9),R^(2b) is selected from B8) or B9), Z is —C(O)—, can be obtained9-i) by reacting a compound of formula (IIb)

R—C(O)—O—R_(a)  (IIb)

wherein R and R_(a) are as above defined with a compound of formula (Ix)

H—X₂₇  (Ix)

wherein X₂₋₇ is the radical selected from (a5′), (a6′), (a9′), (a10′),(b5′), (b6′), (b9′) or (b10′), wherein R^(1b) is selected from A8) orA9), R^(2b) is selected from B8) or B9), and 9-ii) when Q is Z₂, byconverting the compound obtained in the step 9-i) into nitro derivativeby reaction with a nitrate source as above described and9-iii) optionally deprotecting the compounds obtained in step 9-i) or9-ii) as above described.

The reaction of a compound of formula (Ix) wherein X₂₇ and is as abovedefined, with a compound of formula (IIb) wherein R is as above defined,may be carried out as described in 1l-i).

Example 1 Synthesis of(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-((2-(4-(nitrooxy)butyloxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-2-((tert-butylcarbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

To a solution of beclomethasone (0.6 g, 1.46 mmol) in acetone (35 ml),N-Boc-glycine (0.334 g, 1.90 mmol) and DMAP (cat. amount) were added.The reaction was cooled at 0° C. and EDAC (0.365 g, 1.90 mmol) wasadded. The reaction was stirred at room temperature for 2 hours. Thesolvent was evaporated under vacuum. The residue was treated with water(50 ml) and methylene chloride (50×3 ml), the organic layers were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography, eluent n-hexane/ethyl acetate 6/4.The product (0.8 g) was obtained.

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-2-((carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dionehydrochloride

A solution of compound A (0.8 g, 0.41 mmol) in methylene chloride (70ml) was stirred at room temperature. HCl gas was buddle in the solutionfor 1 hour. The solvent was evaporated under reduced pressure. Theproduct was used in the next step without any purification.

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-(2-((4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

To a solution of B) (0.75 g, 1.46 mmol) in methylene chloride (40 ml),4-nitrooxybutyrric acid pentafluorophenyl ester (0.41 g, 1.46 mmol),DMAP (cat. amount) and triethylamine (0.3 ml, 2.19 mmol) were added. Thereaction was stirred at room temperature for 24 hours. The solution wastreated with a 5% solution of H₃PO₄ (50 ml). The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography, (Biotage System, column FLASH40+M® KP-Sil) eluent:gradient n-hexane/ethyl acetate 1/1 (130 ml), toethyl acetate 100% during 130 ml, ethyl acetate 100% (130 ml). Theproduct (0.62 g) was obtained as white powder.

¹H-NMR: (DMSO), δ 8.42 (1H, t); 7.30 (1H, d); 6.22 (1H, dd); 5.98 (1H,s); 5.46 (1H, d); 5.42 (2H, s); 5.05 (1H, d); 4.84 (1H, d); 4.5 (2H, t);4.34 (1H, sb); 3.97 (2H, d); 2.71-2.57 (2H, m); 2.5-2.2 (6H, m); 2.0-1.7(5H, m); 1.65-1.35 (5H, m); 1.25-0.97 (4H, m); 0.8 (3H, s).

Example 2 Synthesis of(11β,16β)-9-Fluoro-11,17-dihydroxy-16-methyl-21-[1-oxo-(2-((4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

The compound was synthesized using the procedure described in example 1starting from betamethasone, Boc-glycine and 4-nitrooxybutyric acidpentafluorophenol ester.

¹H-NMR: (DMSO), δ: 8.4 (1H, t); 7.28 (1H, d); 6.22 (1H, dd); 6.0 (1H,s); 5.30 (1H, d); 5.08 (1H, d); 4.83 (1H, d); 4.53 (2H, t); 4.15 (1H,bp); 3.95 (2H, d); 2.71-2.52 (1H, m); 2.51-2.4 (6H, m); 2.38-2.07 (2H,m); 2.03-1.75 (6H, m); 1.58-1.45 (4H, m), 1.11-0.8 (6H, m).

Example 3 Synthesis of(11β,16β)-9-Fluoro-11-hydroxy-16,17-(1-methylethylidenebis(oxy))-21-[1-oxo-(2-(4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

The compound was synthesized using the procedure described in example 1starting from triamcinolone acetonide, Boc-glycine and 4-nitrooxybutyricacid pentafluorophenol ester.

¹H-NMR: (DMSO), δ□: 8.43 (1H, t); 7.27 (1H, d); 6.21 (1H, dd); 6.0 (1H,s); 5.46 (1H, d); 5.18 (1H, d); 4.87-4.83 (1H, m); 4.74 (1H, d); 4.50(1H, t); 4.18 (1H, sb); 3.98-3.96 (2H, m); 2.71-2.31 (5H, m); 2.30-2.2(3H, m); 2.10-1.77 (6H, m); 1.75-1.42 (7H, m); 1.4-1.32 (4H, m); 1.12(3H, s); 0.85 (3H, s).

Example 4 Synthesis of(6α,11β,16α)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-21-[1-oxo-(2-((4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

The compound was synthesized using the procedure described in example Istarting from fluocinolone acetonide, Boc-glycine and 4-nitrooxybutyricacid pentafluorophenol ester.

¹H-NMR: (DMSO), δ□:: 8.43 (1H, t); 7.25 (1H, d); 6.28 (1H, dd); 6.09(1H, s); 5.75-5.48 (2H, m); 5.18 (1H, d); 4.83 (1H, d); 4.78 (1H, d);4.50 (2H, t); 4.18 (1H, sb); 3.9-3.8 (2H, m); 2.72-2.48 (4H, m); 2.25(2H, t); 2.10-1.8 (3H, m); 1.78-1.65 (1H, m); 1.62-1.51 (2H, m); 1.48(3H, s); 1.32 (3H, s); 1.10 (3H, s); 0.8 (3H, s).

Example 5 Synthesis of 4-(nitrooxy)butyl2-acetamido-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

D) 4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate

To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) in N,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) wasadded. The reaction was cooled at 0° C. and a solution of 4-bromobutylnitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was addeddrop wise. The reaction was stirred at 0° C. for 20 minutes and then atroom temperature for 22 hours. The mixture was poured into a 5% aqueousNaH₂PO₄ solution and extracted with diethyl ether (40×4 ml), the organiclayers were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography, (BiotageSystem, column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethylacetate 9/1 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml,n-hexane/ethyl acetate 1/1 (1000 ml)). The product (3.91 g) wasobtained.

E) 4-(nitrooxy)butyl 2-amino-3-(4-hydroxyphenyl)propanoate

A solution of compound D (0.96 g, 2.41 mmol) in dichloromethane (20 ml)was stirred at room temperature. HCl gas was buddle in the solution for3 hours. The mixture was diluted with dichloromethane (25 ml), washedwith saturated aqueous sodium carbonate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The product(0.71 g) was used in the next step without any purification.

F) 4-(nitrooxy)butyl 2-acetamido-3-(4-hydroxyphenyl)propanoate

To a solution of compound E (0.63 g, 2.25 mmol) in dichloromethane (15ml) triethylamine (0.31 ml, 2.25 mmol) was added. The reaction wascooled at 0° C. and acetyl chloride (0.17 ml, 2.48 mmol) was added dropwise. The reaction was stirred at 0° C. for 10 minutes and then at roomtemperature for 16 hours. The mixture was diluted with dichloromethane(25 ml), washed with water. The organic layer was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography, (Biotage System, column FLASH 25+M™KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (100 ml), ton-hexane/ethyl acetate 2/8 during 1200 ml). The product (0.54 g) wasobtained.

G) 4-(nitroooxy)butyl2-acetamido-3-(4-((4-nitrophenoxy)carbonyloxy)phenyl)propanoate

To a solution of compound F (0.54 g, 1.58 mmol) in dichloromethane (8ml) pyridine (0.15 ml, 1.58 mmol) was added. The reaction was cooled at0° C. and p-nitrophenylchloroformate (320 mg, 1.58 mmol) was added. Thereaction was stirred at 0° C. for 15 minutes and then at roomtemperature for 48 hours. The mixture was diluted with dichloromethane(25 ml), washed with 1M aqueous HCl solution and then with saturatedaqueous sodium carbonate. The organic layers was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography, (Biotage System, column FLASH 25+M™KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (150 ml), ton-hexane/ethyl acetate 3/7 during 1200 ml, n-hexane/ethyl acetate 3/7(600 ml)). The product (0.59 g) was obtained.

H) 4-(nitrooxy)butyl2-acetamido-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

To a solution of compound G (0.55 g, 1.09 mmol) in dichloromethane (12ml), scandium triflate (0.05 g, 0.11 mmol) and DMAP (0.26 g, 2.19 mmol)were added. The reaction was cooled at 0° C. and triamcinolone acetonide(0.47 g, 1.09 mmol) was added. The reaction was stirred at roomtemperature for 18 hours. The mixture was diluted with dichloromethane(24 ml), washed with 5% NaH₂PO₄ and then with saturated aqueous sodiumcarbonate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography, (Biotage System, column FLASH 25+M™ KP-Sil,eluent:gradient n-hexane/ethyl acetate 9/1 (150 ml), to n-hexane/ethylacetate 2/8 during 1200 ml, n-hexane/ethyl acetate 2/8 (800 ml)). Theproduct (0.29 g) was obtained.

¹H-NMR: (DMSO), δ: 8.36 (1H, d); 7.37-7.32 (3H, m); 7.21-7.12 (2H, m);6.23 (1H, dd); 6.02 (1H, s); 5.47 (1H, d); 5.31 (1H, d); 4.97-4.87 (2H,m); 4.59-4.48 (3H, m); 4.27-4.17 (1H, sb); 4.11-3.97 (2H, m); 3.10-2.90(1H, m); 2.71-2.29 (4H, m); 2.10-1.75 (5H, m); 1.60-1.40 (7H, m); 1.38(3H, s); 1.12 (3H, s); 0.80 (3H, s).

Example 6 Synthesis of (2S)-4-(nitrooxy)butyl2-acetamido-3-(4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

The compound was synthesized using the procedure described in example 5starting from fluocinolone acetonide and compound G.

¹H-NMR: (DMSO), δ: 8.36 (1H, d); 7.28 (3H, m); 7.09 (2H, m); 6.30 (1H,dd); 6.11 (1H, d); 5.56 (1H, d); 5.31 (1H, d); 4.91 (2H, m); 4.50 (2H,t); 4.93 (1H, m); 4.25 (1H, m); 4.02 (3H, t); 2.96 (2H, m); 2.27 (1H,m); 2.01 (3H, m); 1.90-1.25 (17H, m); 1.15 (3H, s); 0.80 (3H, s).

Example 7 Synthesis of (2S)-4-(nitrooxy)butyl2-amino-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoatehydrochloride

I) 4-hydroxybutyl2-(tert-butoxycarbonylamino)-3-(4-((4-nitrophenoxy)carbonyloxy)phenyl)propanoate

To a solution of compound D (1.97 g, 4.86 mmol) in dichloromethane (24ml) pyridine (0.48 ml, 4.86 mmol) was added. The reaction was cooled at0° C. and p-nitrophenylchloroformate (980 mg, 4.86 mmol) was added. Thereaction was stirred at 0° C. for 10 minutes and then at roomtemperature for 21 hours. The mixture was diluted with dichloromethane(25 ml), washed with 1M aqueous HCl solution and then with saturatedaqueous sodium carbonate. The organic layers was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography, (Biotage System, column FLASH 40+M™KP-Sil, eluent:gradient n-hexane/ethyl acetate 98/2 (200 ml), ton-hexane/ethyl acetate 6/4 during 1600 ml, n-hexane/ethyl acetate 6/4(300 ml)). The product (2.19 g) was obtained.

J) (2S)-4-(nitrooxy)butyl2-(tert-butoxycarbonylamino)-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

To a solution of compound I (1.35 g, 2.4 mmol) in dichloromethane (40ml), scandium triflate (0.11 g, 0.24 mmol) and DMAP (0.57 g, 4.8 mmol)were added. The reaction was cooled at 0° C. and triamcinolone acetonide(1.25 g, 2.88 mmol) was added. The reaction was stirred at roomtemperature for 70 hours. The solvent was evaporated under reducedpressure. The residue was purified by flash chromatography, (BiotageSystem, column FLASH 40+M™ KP-Sil, eluent:gradient n-hexane/ethylacetate 9/1 (200 ml), to n-hexane/ethyl acetate 3/7 during 1600 ml,n-hexane/ethyl acetate 3/7 (500 ml)). The product (0.98 g) was obtained.

K)(2S)-4-(nitrooxy)butyl-2-amino-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate hydrochloride

A solution of compound J (1.42 g, 1.65 mmol) in dichloromethane (28 ml)was stirred at room temperature. HCl gas was buddle in the solution for15 minutes. The mixture was diluted with dichloromethane (35 ml), washedwith saturated aqueous sodium carbonate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by reverse-phase flash chromatography, (Biotage System,column FLASH 40+M™ KP-Sil, eluent:gradient water/acetonitrile 9/1 (150ml), to water/acetonitrile 2/8 during 1400 ml, water/acetonitrile 2/8(200 ml)). The free base of product M (0.67 g) was treated with asolution of HCl in diethyl ether. The hydrochloride salt of compound Mwas filtered and dried under vacuum. The product (0.57 g) was obtained.

¹H-NMR: (DMSO), δ: 8.57 (2H, m); 7.38-7.29 (3H, m); 7.22-7.19 (2H, m);6.22 (1H, dd); 6.00 (1H, s); 5.54 (1H, d); 5.31 (1H, d); 4.88-4.84 (2H,m); 4.52-4.40 (2H, m); 4.25-4.20 (1H, sb); 4.16-4.09 (3H, m); 3.22-3-04(1H, m); 2.71-2.29 (4H, m); 2.10-1.75 (5H, m); 1.60-1.34 (7H, m); 1.13(3H, s); 0.82 (3H, s).

Example 8 Synthesis of (2S)-4-(nitrooxy)butyl2-amino-3-(4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoatehydrochloride

The compound was synthesized using the procedure described in example 7starting from fluocinolone acetonide and compound I.

¹H-NMR: (DMSO), δ: 8.64 (2H, s); 7.41-7.35 (3H, m); 7.23 (2H, d); 6.30(1H, dd); 6.11 (1H, s); 5.80-5.50 (2H, m); 5.40-5.27 (1H, m); 5.00-4.75(2H, m); 4.53-4.45 (2H, m); 4.48-4.05 (4H, m); 3.31-3.03 (2H, m);2.75-2.60 (1H, m); 2.27 (1H, sb); 2.11-1.98 (3H, m); 1.82-1.52 (5H, m);1.50 (3H, s); 1.38 (3H, s); 1.10 (3H, s); 0.81 (3H, s).

Example 9 Synthesis of2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-(1-methylethylidenebis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-2-(5-(nitrooxy)pentanamido)acetate

The compound was synthesized using the procedure described in example Istarting from triamcinolone acetonide, Boc-glycine and 4-nitrooxybutyricacid pentafluorophenol ester.

¹H-NMR: (DMSO), δ: 7.29 (1H, d); 6.23 (1H, dd); 6.02 (1H, s); 5.48 (1H,d); 5.20 (1H, d); 4.86 (1H, m); 4.78 (1H, d); 4.50 (2H, t); 4.18 (1H,sb); 3.98-3.96 (2H, m); 2.71-2.25 (2H, m); 2.30 (5H, m); 1.75-1.42 (14H,m); 1.4-1.32 (4H, m); 1.12 (3H, s); 0.83 (3H, s).

Example 10 Synthesis of2-((8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl2-(5-(nitrooxy)hexanamidoamido) acetate

The compound was synthesized using the procedure described in example Istarting from betamethasone, Boc-glycine and 6-nitrooxyhexanoic acidpentafluorophenol ester.

¹H-NMR: (DMSO), δ: 8.28 (1H, t); 7.27 (1H, d); 6.15 (1H, dd); 5.99 (1H,s); 5.35 (1H, s); 5.27 (1H, d); 4.99 (1H, d), 4.79 (1H, d); 4.48 (2H,t), 4.11 (1H, m); 3.91 (2H, d); 2.60 (1H, m); 2.50-2.30 (2H, m); 2.10(4H, m); 2.00-1.80 (3H, m); 1.70-1.30 (11H, m); 1.00 (4H, d); 0.99 (3H,s).

Example 11 Synthesis of2-((6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-dimethoxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl2-(6-nitrooxyhexanamido) acetate

The compound was synthesized using the procedure described in example Istarting from fluocinolone acetonide, Boc-glycine and 6-nitrooxyhexanoicacid pentafluorophenol ester.

¹H-NMR: (DMSO), δ: 8.32 (1H, t); 7.25 (1H, d); 6.28 (1H, dd); 6.09 (1H,s); 5.74-5.50 (2H, m); 5.18 (1H, d); 4.85 (1H, d); 4.78 (1H, d); 4.48(2H, t); 4.19 (1H, sb); 3.94 (2H, m); 2.63-2.48 (1H, m); 2.25 (1H, t);2.13 (2H, t); 2.10-1.93 (2H, m); 1.73-1.40 (11H, m); 1.30 (5H, m); 1.10(3H, s); 0.8 (3H, s).

Example 12 Synthesis of1-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl)2-acetamido pentanedioate

L)2-acetamido-4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)-4-oxobutanoicacid

To a solution of triamcinolone acetonide (3.1 g, 7.13 mmol) in acetone(100 ml), N-acetyl aspartic acid (2.0 g, 11.42 mmol) and DMAP (cat.amount) were added. The reaction was cooled at 0° C. and EDAC(2.18 g,11.42 mmol) was added. The reaction was stirred at room temperature for24 hours. The solvent was evaporated under vacuum. The residue waspurified by flash chromatography (Biotage System, column FLASH 65+M™KP-Sil, eluent:gradient dichloromethane/methanol 95/5 (675 ml), todichloromethane/methanol 9/1 during 3600 ml, dichloromethane/methanol9/1 (900 ml)). The product (2.67 g) was obtained.

M) 1-(4-chlorobutyl)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-acetamidosuccinate

To a solution of compound L (0.6 g, 1.31 mmol) in dichloromethane (30ml), 4-chlorobutanol (0.13 ml, 1.31 mmol) and DMAP (cat. amount) wereadded. The reaction was cooled at 0° C. and EDAC(0.25 g, 1.31 mmol) wasadded. The reaction was stirred at room temperature for 24 hours. Thesolvent was evaporated under vacuum. The residue was purified by flashchromatography (Biotage System, column FLASH 25+M™ KP-Sil,eluent:gradient n-hexane/ethyl acetate 6/4 (60 ml), to n-hexane/ethylacetate 2/8 during 600 ml, to ethyl acetate during 60 ml, ethyl acetate(180 ml)). The product (0.65 g) was obtained.

N) 1-(4-iodobutyl)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-acetamidosuccinate

To a solution of compound M (0.55 g, 0.76 mmol) in acetonitrile (18 ml),sodium iodide (0.45 g, 3.06 mmol) was added. The reaction was heated to120° C. for 60 minutes under microwave irradiation. The resultingmixture was cooled, filtered and the solvent was removed under reducedpressure to give a solid product which was used without furtherpurification.

O)1-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl)2-acetamidopentanedioate

To a solution of compound N (0.60 g, 0.76 mmol) in acetonitrile (20 ml),silver nitrate (0.51 g, 3.06 mmol) was added. The reaction was heated to120° C. for 5 minutes under microwave irradiation. The resulting mixturewas cooled, filtered and the solvent was removed under reduced pressure.The residue was purified by flash chromatography (Biotage System, columnFLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 4/6 (60 ml),to ethyl acetate 100% during 480 ml, ethyl acetate (120 ml)). Theproduct (0.40 g) was obtained.

¹H-NMR: (DMSO): 8.45 (1H, d); 7.26 (1H, d); 6.22 (1H, dd); 6.00 (1H, s);5.48 (1H, m); 5.12 (1H, dd), 4.84-4.76 (3H, m); 4.52 (2H, t); 4.20 (1H,m), 4.06 (2H, m); 2.87 (1H, dm); 2.75-2.48 (3H, m); 2.10-1.75 (4H, m);1.82 (3H, s); 1.50-1-70 (7H, m); 1.47 (3H, s); 1.33 (4H, m); 1.15 (3H,s); 0.83 (3H, s).

Example 13 Synthesis of2-((8S,9R,10S,11S,3S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl3-(6-(nitrooxy)hexanamido) propanoate

The compound was synthesized using the procedure described in example Istarting from betamethasone, Boc-beta-alanine and 6-nitrooxyhexanoicacid pentafluorophenol ester.

¹H-NMR: (DMSO), δ: 7.88 (1H, t); 7.29 (1H, d); 6.22 (1H, dd); 6.01 (1H,s); 5.36 (1H, s); 5.31 (1H, d); 5.01 (1H, d); 4.84 (1H, d); 4.50 (2H,t); 4.15 (1H, sb); 3.48-3.25 (2H, m); 2.75-2.25 (7H, m); 2.20-2.00 (4H,m); 1.99-1.75 (4H, m); 1.71-1.61 (2H, m); 1.57-1.48 (5H, m); 1.42-1.27(2H, m); 1.01 (3H, d); 0.90 (3H, s).

Example 14 Synthesis of2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-dimethoxy-10,13-((1-methylethylidene)bis(oxy))-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-3-(6-(nitrooxy)hexanamido)propanoate

The compound was synthesized using the procedure described in example Istarting from triamcinolone acetonide, Boc-beta-alanine and6-nitrooxyhexanoic acid pentafluorophenol ester.

¹H-NMR: (DMSO), δ: 8.31 (1H, t); 7.30 (1H, d); 6.24 (1H, dd); 6.01 (1H,s); 5.49 (1H, d); 5.25 (1H, d); 4.86 (1H, d); 4.75 (1H, d); 4.50 (2H,t); 4.19 (1H, sb); 3.93 (2H, m); 2.75-2.25 (2H, m); 2.15 (2H, t);2.10-1.75 (3H, m); 1.75-1.45 (7H, m); 1.47 (3H, s); 1.40-1.20 (6H, m);1.17 (5H, m); 0.80 (3H, s).

Example 15 Synthesis of2-((6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-3-(6-(nitrooxy)hexanamido) propanoate

The compound was synthesized using the procedure described in example Istarting from fluocinolone acetonide, Boc-beta-alanine and6-nitrooxyhexanoic acid pentafluorophenol ester.

¹H-NMR: (DMSO), δ: 7.91 (1H, t); 7.27 (1H, d); 6.30 (1H, dd); 6.11 (1H,s); 5.75-5.50 (2H, m); 5.16 (1H, d); 4.85-4.90 (1H, m); 4.76 (1H, d);4.61-4.48 (2H, t); 4.22 (1H, sb); 3.40-3.25 (3H, m); 2.70-2.50 (4H, m);2.40-2.30 (1H, m); 2.15-1.93 (2H, m); 1.80-1.45 (10H, m); 1.41-1.28 (5H,m); 1.21 (3H, s); 0.82 (3H, s).

Example 16 Synthesis of4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl)2-(6-(nitrooxy)hexanamido)succinate

P) 1-allyl4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-(tert-butoxycarbonylamino) succinate

To a solution of triamcinolone acetonide (3.0 g, 6.9 mmol) indichloromethane (100 ml),4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoic acid (1.88 g,6.9 mmol) and DMAP (cat. amount) were added. The reaction was cooled at0° C. and EDAC(1.7 g, 8.97 mmol) was added. The reaction was stirred atroom temperature for 12 hours. The solvent was evaporated under vacuum.The residue was purified by flash chromatography (Biotage System, columnFLASH 40+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 8/2 (300ml), to n-hexane/ethyl acetate 4/6 during 900 ml, n-hexane/ethyl acetate4/6 (300 ml)). The product (4.16 g) was obtained.

Q) 1-allyl4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-(amino)succinatehydrochloride

A solution of compound P (1.0 g, 1.45 mmol) in dichloromethane (28 ml)was stirred at room temperature. HCl gas was buddle in the solution for15 minutes. The solvent evaporated under vacuum to give a solid productwhich was used without further purification.

R) 1-allyl4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(6-(nitrooxy)hexanamido)succinate

To a solution of compound Q (0.91 g, 1.45 mmol) in dichloromethane (100ml), DMAP (0.26 g, 2.17 mmol) and 6-nitrooxyhexanoic acidpentafluorophenol ester (0.49 g, 1.45 mmol) were added. The reaction wasstirred at room temperature for 12 hours. The solvent was evaporatedunder reduced pressure. The residue was purified by flashchromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 1/1 (150 ml), to ethyl acetate during900 ml, ethyl acetate (450 ml)). The product (0.64 g) was obtained.

S)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(6-(nitrooxy)hexanamido)-4-oxobutanoicacid

To a solution of compound R (0.58 g, 0.77 mmol) in dichloromethane (20ml), 5,5-cimethyl-1,3-cyclohexanedione (0.13 g, 0.97 mmol),triphenylphosphine (0.30 g, 1.16 mmol) andtetrakis(triphenylphosphine)palladium (0.045 g, 0.039 mmol) were added.The reaction was stirred at room temperature for 12 hours. The solventwas evaporated under reduced pressure. The residue was purified by flashchromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent:n-hexane/acetone/acetic acid 4/6/0.1%) The product (0.31 g) wasobtained.

T)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(chloro)butyl)2-(6-(nitrooxy)hexanamido)succinate

To a solution of compound S (0.33 g, 0.47 mmol) in dichloromethane (20ml), 4-chlorobutanol (0.06 ml, 0.61 mmol) and DMAP (cat. amount) wereadded. The reaction was cooled at 0° C. and EDAC(0.12 g, 0.62 mmol) wasadded. The reaction was stirred at room temperature for 24 hours. Thesolvent was evaporated under vacuum. The residue was purified by flashchromatography (Biotage System, column FLASH 25+M™ KP-Sil,eluent:gradient n-hexane/ethyl acetate 6/4 (60 ml), to n-hexane/ethylacetate 2/8 during 360 ml, n-hexane/ethyl acetate 2/8 (240 ml)). Theproduct (0.25 g) was obtained.

U)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)1-(4-(iodo)butyl) 2-(6-(nitrooxy)hexanamido)succinate

To a solution of compound T (0.25 g, 0.31 mmol) in acetonitrile (10 ml),sodium iodide (0.18 g, 1.25 mmol) was added. The reaction was heated to120° C. for 60 minutes under microwave irradiation. The resultingmixture was cooled, filtered and the solvent was removed under reducedpressure to give a solid product which was used without furtherpurification.

V)4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl)2-(6-(nitrooxy)hexanamido)succinate

To a solution of compound U (0.27 g, 0.31 mmol) in acetonitrile (10 ml),silver nitrate (0.21 g, 1.24 mmol) was added. The reaction was heated to120° C. for 5 minutes under microwave irradiation. The resulting mixturewas cooled, filtered and the solvent was removed under reduced pressure.The residue was purified by flash chromatography (Biotage System, columnFLASH 25+M™ KP-Sil, eluent:gradient n-hexane/acetone 8/2 (120 ml), ton-hexane/acetone 55/45 during 480 ml, n-hexane/acetone 55/45 (120 ml)).The product (0.13 g) was obtained.

¹H-NMR: (DMSO), δ: 7.18 (1H, d); 6.59 (1H, d); 6.32 (1H, dd); 6.13 (1H,s); 5.02-4.88 (4H, m); 4.51-4.40 (5H, m); 4.27-4.11 (2H, m); 3.05 (1H,dd); 2.90 (1H, dd); 2.68-2.30 (4H, m); 2.27 (2H, t); 2.27-2.00 (2H, m);1.90-1.40 (18H, m); 1.21 (3H, s); 0.88 (3H, s).

Example 17 Synthesis of 1-(2,3-bis(nitrooxy) propyl)4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-aminosuccinatehydrochloride

W) 1-allyl-4-(4-nitrophenyl)-2-(tert-butoxycarbonylamino) succinate

To a solution of 4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoicacid (3.0 g, 11.0 mmol) in dichloromethane (50 ml), 4-nitrophenol (1.4g, 11.0 mmol) and DMAP (cat. amount) were added. The reaction was cooledat 0° C. and EDAC(2.85 g, 15.0 mmol) was added. The reaction was stirredat room temperature for 12 hours. The solvent was evaporated undervacuum. The residue was purified by flash chromatography (BiotageSystem, column FLASH 65+M™ KP-Sil, eluent:gradient n-hexane/ethylacetate 95/5 (450 ml), to n-hexane/ethyl acetate 6/4 during 4500 ml,n-hexane/ethyl acetate 6/4 (900 ml)). The product (1.5 g) was obtained.

X) 1-(2,3-bis(nitrooxy)propyl) 4-(4-nitrophenyl)2-(tert-butoxycarbonylamino)succinate

To a solution of compound W (1.5 g, 3.8 mmol) in acetonitrile (60 ml),silver nitrate (0.63 g, 3.8 mmol) was added. The reaction was cooled at−15° C. and iodine (0.96 g, 3.8 mmol) was added. The reaction wasstirred at 0° C. for 1 hour. Silver nitrate (1.27 g, 7.6 mmol) was addedand the mixture was stirred at 70° C. for 7 days adding silver nitrate(0.96 g, 3.8 mmol) every day. The solvent was evaporated under vacuum.The residue was purified by flash chromatography (Biotage System, columnFLASH 65+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 95/5 (450ml), to n-hexane/ethyl acetate 6/4 during 4500 ml, n-hexane/ethylacetate 6/4 (900 ml)). The product (0.54 g) was obtained.

Y) 1-(2,3-bis(nitrooxy)propyl)4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(tert-butoxycarbonylamino)succinate

To a solution of triamcinolone acetonide (0.21 g, 0.5 mmol) indichloromethane (13 ml), compound X (0.26 g, 0.5 mmol) and DMAP (0.06 g,0.5 mmol)) were added. The reaction was stirred at room temperature for12 hours. The solvent was evaporated under vacuum. The residue waspurified by flash chromatography (Biotage System, SNAP Cartridge silica100 g, eluent: gradient n-hexane/ethyl acetate 88/12 (150 ml), to ethylacetate during 1500 ml, ethyl acetate (300 ml)). The product (0.4 g) wasobtained.

Z) 1-(2,3-bis(nitrooxy)propyl)4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-aminosuccinate hydrochloride

A solution of compound Y (0.4 g, 0.49 mmol) in dichloromethane (8 ml)was stirred at room temperature. HCl gas was buddle in the solution for15 minutes. The solvent evaporated under vacuum. The residue waspurified by reverse phase flash chromatography (Biotage column FLASH25+M™, eluent: water/acetonitrile 1/1. The product (0.13 g) was obtained

¹H-NMR: (DMSO), δ: 7.30 (1H, d); 6.23 (1H, dd); 6.02 (1H, s); 5.66 (1H,m); 5.49 (1H, m); 5.17 (1H, dd), 4.97 (1H, dd); 4.89-4.79 (3H, m); 4.48(1H, dm); 4.38 (1H, dd), 4.20 (1H, m); 3.82 (1H, m); 2.78 (1H, dm);2.68-2.49 (7H, m); 2.10-1.75 (3H, m); 1.54 (1H, m); 1.49 (5H, m); 1.35(4H, m); 1.15 (3H, s); 0.83 (3H, s).

1. A compound of general formula (I) and pharmaceutically acceptablesalts or stereoisomers thereofR—(Z)_(a)—R_(x)  (I) wherein R is a corticosteroid residue of formula(II):

wherein: R₁ is OH, R₂ —CH₃, or R₁ and R₂ are taken together to form agroup of formula (III)

R₃ is CI or F; R₄ is H or F; wherein R₁, R₂, R₃ and R₄ can be linked tothe correspondent carbon atoms of the steroidal structure in position αor β; with the proviso that: when R₁ and R₂ are the group of formula(III) then R₃ is F and R₄ is H or F; when R₁ is OH and R₂ —CH₃ then R₄is H and R₃ is CI or F; preferred corticosteroid radicals are R offormula (II) wherein: R₁ is OH in position α, R₂ —CH₃ in position β, R₃is CI in position α and R₄ is H; or R₁ is OH in position α, R₂ —CH₃ inposition β, R₃ is F in position α and R₄ is H; or R₁ and R₂ are takentogether to form a group of formula (III)

R₃ is F and R₄ is H, R₁, R₂ and R₃ are in position α; or R₁ and R₂ aretaken together to form a group of formula (III)

R₃ and R₄ are F, R₁, R₂, R₃ and R₄ are in position α; a in formula (I)is equal to 0 or 1; Z is a group capable of binding R_(x) and isselected from —C(O)—, or CH(R′)—O— wherein R′ is selected from H or astraight or branched C₁-C₄ alkyl; R_(x) is a radical and is selectedfrom the the following meanings: A)—HN—CH(R¹)—C(O)-(T-Y—ONO₂)  (a1)—C(O)—CH(R¹)—NH-(T′-Y—ONO₂)  (a2)—HN—CH(R^(1a)-T″-Y′—ONO₂)—COOR^(3a)  (a3)—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NHR^(4a)  (a4)—R^(1b)—CH(NHR^(4a)—C(O)-(T-Y—ONO₂)  (a5)—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)—HN—CH(R^(1a)-T″-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a7)—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a8)—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9) wherein: R¹ is selectedfrom: A1) H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl,methylthio-(CH₂)₂—, phenyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstitutedbenzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl whereinthe substituent of the benzyl is selected from —F, —Cl, —I, —NO₂, —CF₃,—CH₃, CN, C₆H₅CO—; 2,4-dichlorobenzyl, 3,4-dichlorobenzyl,3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH₂—,3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—, 9-anthranyl-CH₂—, cyclohexyl,cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—,4-B(OH)₂-benzyl, 4-quinolyl-CH₂—, 3-quinolyl-CH₂—, 2-quinolyl-CH₂—,2-quinoxalyl-CH₂—, 2-furyl-CH₂—, 1-naphtyl-CH₂—, 2-naphtyl-CH₂—,2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 2-thienyl-CH₂—,3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—, CH≡CH—CH₂—, NH₂—CO—CH₂—,NH₂—CO—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, P(═O)(OCH₃)₂, I—CH₂—; A2) —CH₂—SH,—CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)],—CH₂-[(C₆H₂)-(3,5-diiodo)-(4-OH)], —CH₂-[(C₆H₃)-(3-nitro)-(4-OH)]; A3)—CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H,—C(O)CH₃ or

wherein R^(5a) is H or a linear or branched C₁-C₁₀ alkyl chain,preferably R^(5a) is H or a linear (C₁-C₅) alkyl, wherein R″ is as abovedefined; A4) —CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″is —OR^(5a) or

wherein R^(5a) is as above defined, wherein R′″ is as above defined;R^(1a) is selected from, A5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—,—CH₂[(C₆H₄)-(4-O)], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)],—CH₂-[(3-nitro)-(C₆H₃)-(4-O)—]; A6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—,—(CH₂)₄—NH—; A7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; R^(3a) isselected from H, —R^(5a) or

wherein R^(5a) is as above defined; R^(4a) is selected from H or—C(O)CH₃ or

wherein R^(5a) is as above defined; R^(1b) is selected from A8) —S—CH₂—,—O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—,[-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—; A9)—HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—; A10) —C(O)—CH₂—,—C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—; T is selected from —O—, —S—, —NR′—,O—CH(R′)—O—C(O)— or O—CH(R′)—O—C(O)O— wherein R′ is as above defined; T′is C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is C(O)—NR′— whereinR′ is as above defined; T″ is independently selected from C(O)—,—C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, O—CH(R′)—O—C(O)—,O—CH(R′)—O—C(O)O—, wherein X″ and R′ are as above defined, with theproviso that T″ is —C(O)—, —C(O)—X″— or C(O)—NR′— when T″ is linked to—NH—, —O—, or —S—; or T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—,—O—CH(R′)—O—C(O)O— when T″ is linked to C(O)—; Y and Y′ are as belowdefined; B)—HN—CH(R²)—CH₂C(O)-(T-Y—ONO₂)  (b1)—C(O)—CH₂—CH(R²)—NH-(T-Y—ONO₂)  (b2)—HN—CH(R^(2a)-T″-Y—ONO₂)—CH₂COOR^(3a)  (b3)—C(O)—CH₂—CH(R^(2a)-T″-Y—ONO₂)—NHR^(4a)  (b4)—R^(2b)—CH(NHR^(4a)—CH₂C(O)-(T-Y—ONO₂)  (b5)—R^(2b)—CH(CH₂COOR^(3a))NH-(T′-Y—ONO₂)  (b6)—HN—CH(R^(2a)-T″-Y′—ONO₂)—CH₂—C(O)-(T-Y—ONO₂)  (b7)—C(O)—CH₂—CH(R^(2a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (b8)—R^(2b)—CH(NH-T′-Y′—ONO₂)—CH₂C(O)-(T-Y—ONO₂)  (b9)—R^(2b)—CH(CH₂C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (b10) wherein R² isselected from B1) H, —CH₃, CF₃, isopropyl, isobutyl, sec-butyl,methylthio-(CH₂)₂—, phenyl, benzyl, 3-triptophanyl-CH₂—, NH₂—C(O)—CH₂—,NH₂—C(O)—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, tBuO—CH(CH₃)—, benzyl-O—CH₂—,4-terbutoxy-benzyl, 4-phenylbenzyl; B2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH,—CH₂[(C₆H₄)-(4-O)—], —CH₂-[(C₆H₂)-(3,5-diiodo)-(4-OH)],—CH₂-[(C₆H₃)-(3-nitro)-(4-OH)]; B3) —CH₂—NHR″, —(CH₂)₂—NHR″,—(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is as above defined; B4)—CH₂—C(O)—R′″, —(CH₂)₂—C(O)—R′″, —(CH₂)₄—C(O)—R′″ wherein R′″ is asabove defined; R^(2a) is selected from B5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—or —CH₂[(C₆H₄)-(4-O)], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)],—CH₂-[(3-nitro)-(C₆H₃)-(4-O)—]; B6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—,—(CH₂)₄—NH—; B7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O); R^(2b) isselected from B8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—,[-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—; B9)—HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—; B10) —C(O)—CH₂—,—C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—; R^(3a) and R^(4a) are as above defined; T,T′ and T″ are as above defined and Y and Y′ are as below defined; C)—HN(CH₂)_(b)—C(O)-(T-Y—ONO₂);  (c1)—C(O)(CH₂)_(b)—NH-(T′-Y—ONO₂);  (c2) wherein b is an integer from 3 to6, T and T′ are as above defined; D)—HN—CH(R¹²)—CH₂—O-(T′″-Y—ONO₂)  (d1)—O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)  (d2)—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂OH  (d3)—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NHR^(4a)  (d4)—R^(12b)—CH(NHR^(4a))—CH₂—O-(T′″-Y—ONO₂)  (d5)—R^(12b)—CH(CH₂OH)—NH-(T′-Y—ONO₂)  (d6)—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂)  (d7)—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d8)—R^(12b)—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂)  (d9)—R^(12b)—CH(CH₂—O-T′″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d10) wherein T′″ isindependently selected from —C(O)—, —C(O)X″— wherein X″ is —O— or S—, or—C(O)—NR′— wherein R′ is as above defined; T′ and T″ are as abovedefined; Y and Y′ are as below defined; R¹² is selected from: D1) H,—CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl,3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—,NH₂(═NH)NH—(CH₂)₃—; D2) —CH₂—OH, —CH(CH₃)—OH, CH₂[(C₆H₄)-(4-OH)],CH₂-[(C₆H₃)-(3,5-diiodo)-(4-OH)], —CH₂-[(C₆H₃)-(3-nitro)-(4-ON; D3)—CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is asabove defined, preferably R^(u) is —(CH₂)₄—NHR″; D4) —CH₂—C(O)R′″,—(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is as above defined;R^(12a) is selected from D5) —CH₂—O—, —CH(CH₃)—O— or CH₂[(C₆H₄)-(4-O)],—CH₂-[3,5-diiodo-(C₆H₂)-(4-O)], —CH₂-[3-nitro-(C₆H₃)-4-O-]; D6)—CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—; D7) —CH₂—C(O)—,—(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; R^(12b) is selected from D8) —O—CH₂—,—O—CH(CH₃)—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂,[-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—; D9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—,—HN—(CH₂)₄—; D10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—; R^(4a) is asabove defined;

wherein c is equal to 0 or 1, d is an integer from 0 to 3 with theproviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3, Tand T′ are as above defined;

wherein e and f are equal to 0 or 1, with the proviso that f is 0 when eis 0 and f is 0 or 1 when e is 1, T and T′ are as above defined;

wherein R³ is H, CH₃, propyl, (C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl, allyl,2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl,4-bromobenzyl, 4-methylbenzyl, T and T′ are as above defined;

wherein R⁴ is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are asabove defined;

wherein R⁵ is H, R⁶ is H, or R⁵ and R⁶ when taken together are a doublebond, T and T′ are as above defined;

wherein T and T′ are as above defined;

wherein T and T′ are as above defined;

wherein c is as above defined, d is equal to 0 or 1, T and T′ are asabove defined;

wherein R⁷ is H, R⁸ is H, or R⁷ and R⁸ when taken together are a doublebond, c is as above defined, T and T′ are as above defined;

wherein T and T′ are as above defined;

wherein T and T′ are as above defined and;

wherein T and T′ are as above defined;

wherein T and T′ are as above defined;

wherein T and T′ are as above defined;

wherein R⁹ and R¹⁹ are H, CH₃, R¹¹ is CH₃ or 4-piperidinyl with theproviso that R⁹ and R¹⁹ are H when R¹¹ is 4-piperidinyl and R⁹ and R¹⁹are CH₃ when R¹¹ is CH₃, T and T′ are as above defined;

wherein T and T′ are as above defined; with the proviso that in theformula (I): a is 0 or a is 1 and Z is CH(R)—O— wherein R′ is as abovedefined, when R_(x) is: (a2), (a4) or (a8); (a5), (a6), (a9) or (a10)and R^(1b) is selected from the group A10); (b2), (b4) or (b8); (b5),(b6), (b9) or (b10) and R^(2b) is selected from the group B10); (c2);(d5), (d6), (d9) or (d10) and R^(12b) is selected from the group D10);(e2), (f1), (g2), (h1), (i1) (l2), (m2), (n2), (o2), (p2), (q2), (r2),(s2), (t1) or (u2); a is 1 and Z is —C(O)—, when R_(x) is: (a1), (a3) or(a7); (a5), (a6), (a9) or (a10) and R^(1b) is selected from the groupsA8) and A9); (b1), (b3) or (b7); (b5), (b6), (b9) or (b10) and R^(2b) isselected from the groups B8) or B9); (c1); (d1), (d2), (d3), (d4), (d7)or (d8); (d5), (d6), (d9) or (d10) and R^(2b) is selected from thegroups D8) or D9); (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (o1),(p1), (q1), (r1), (s1), (t2) or (u1). Y and Y′ are bivalent radicalseach independently selected from the following meanings: a) straight orbranched C₁-C₂₀ alkylene; straight or branched C₁-C₂₀ alkylenesubstituted with one or more of the substituents selected from the groupconsisting of: halogen atoms, hydroxy, —ONO₂ or T₂, wherein T₂ is—OC(O)(C₁-C₁₀ alkyl)-ONO₂ or —O(C₁-C₁₀ alkyl)-ONO₂; cycloalkylene with 5to 7 carbon atoms into cycloalkylene ring, the ring being optionallysubstituted with one or more straight or branched C₁-C₁₀ alkyl chains;

wherein n⁰ is an integer from 0 to 20; n¹ is 0 or 1; U is a linear orbranched C₁-C₂₀ alkylene optionally substituted with a —ONO₂ group;

wherein n⁰ is an integer from 0 to 20; n¹ is 0 or 1; U is a linear orbranched C₁-C₂₀ alkylene optionally substituted with a —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or —C(O)O—; n¹ and U are as above defined;

n² is an integer from 0 to 2; R¹³ is H or CH₃; Y¹ is CH₂—CH₂— or—CH═CH—(CH₂)_(n) ^(2′)—, wherein n^(2′) is 0 or 1; T₁=—O—C(O)— orC(O)O—; U is a linear or branched C₁-C₂₀ alkylene optionally substitutedwith a —ONO₂ group;

wherein: n² is an integer from 0 to 2, preferably n² is 1; R¹³ is H orCH₃, preferably R¹³ is CH₃; Y¹ is —CH₂—CH₂— or (CH₂)_(n) ^(2′)—CH═CH—,wherein n^(2′) is 0 or 1; (T₁)′=—O—C(O)—; n¹ is 0 or 1; U is a linear orbranched C₁-C₂₀ alkylene optionally substituted with a —ONO₂ group; whenY and Y′ are selected from b), c), d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ -CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH— and n³is an integer from 1 to 6;

wherein: n⁴ is an integer from 0 to 10; n⁵ is an integer from 1 to 10;R¹⁴, R¹⁵, R¹⁶, R¹⁷ are the same or different, and are H or straight orbranched C₁-C₄ alkyl; wherein the —ONO₂ group is linked to

wherein n⁵ is as defined above; Y² is an heterocyclic saturated,unsaturated or aromatic 5 or 6 members ring, containing one or moreheteroatoms selected from nitrogen, oxygen, sulphur, and is selectedfrom the group consisting of:


2. A compound of formula (I) according to claim 1 wherein R, R₁, R₂, R₃and R₄ are as defined in claim 1; a is 0 and R_(x) is selected from:—C(O)—CH(R¹)—NH-(T′-Y—ONO₂)  (a2) wherein R¹ of the group A1) isselected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstitutedbenzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl whereinthe substituent of the benzyl is selected from —F, —Cl, —I, —NO₂, —CF₃,—CH₃, CN, C₆H₅CO—; R¹ of the group A2) is selected from —CH₂—OH,—CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)], or R¹ of the group A3) is selectedfrom —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ isH, or —C(O)CH₃; R¹ of the group A4) is selected from —CH₂—C(O)R′″,—(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is OR^(5a) wherein R^(5a)is H or a linear (C₁-C₅) alkyl; T′ is —C(O)—, —C(O)—X″ wherein X″ is —S—or —O—; or R_(x) is—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NHR^(4a)  (a4) wherein R^(1a) of the groupA5) is selected from —CH₂—O—, —CH(CH₃)O— or —CH₂[(C₆H₄)-(4-O)—], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, or R^(1a) of the group A7) is selected from—CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; R^(4a) is H or —C(O)CH₃; T″ isC(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^(1a) is selected fromthe group A5) or A6); T″ is —O—, —S—, —NR′— or O—CH(R′)—O—C(O)— whereinR′ is H or CH₃, when R^(1a) is selected from the group A7); or R_(x) isselected from—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂)  (a5)—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or  (a9)—R^(1b)—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a10) wherein R^(1b) of thegroup A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—;R^(3a) is H or a (C₁-C₅) alkyl; R^(4a) is H or —C(O)CH₃; T is —O—, —S—,—NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH₃; T′ is C(O)— or—C(O)—X″ wherein X″ is —S— or —O—; or R_(x) is—C(O)—CH(R^(1a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a8) wherein R^(1a) of thegroup A5) is selected from CH₂—O—, —CH(CH₃)—O— or CH₂[(C₆H₄)-(4-O)], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, or R^(1a) of the group A7) is selected from—CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; T″ is C(O)— or —C(O)—X″wherein X″ is —S— or —O—, when R^(1a) is selected from the group A5) orA6)-; T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH₃,when R^(1a) is selected from the group A7); T′ is C(O)— or —C(O)—X″wherein X″ is —S— or —O—; or R_(x) is—C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)  (b2) wherein R² of the group B1) isselected from H, CH₃, isobutyl, isopropyl, benzyl; T′ is —C(O)—,—C(O)—X″ wherein X″ is —S— or —O—; Y and Y′ are each independentlyselected from a) a straight or branched C₁-C₁₀ alkylene, a straight orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or —C(O)O—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linearor branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH—(CH₂)_(n) ^(2′) and n⁷ is 0, T₁ isC(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein: n² is 1, R¹³ is CH₃; Y¹ is (CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is0; (T₁)′=—O—C(O)—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is alinear or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group; whenY and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH—, n³ is1 or
 2. 3. A compound of formula (I) according to claim 1 wherein R, R₁,R₂, R₃ and R₄ are as defined in claim 1, A is 1 and Z is C(O)—, R_(x) is—HN—CH(R¹)—C(O)-(T-Y—ONO₂)  (a1) wherein R¹ of the group A1) is selectedfrom H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or3-monosubstituted benzyl or 4-monosubstituted benzyl wherein thesubstituent of the benzyl is selected from F, —Cl, —I, —NO₂, —CF₃, —CH₃,CN, C₆H₅CO—; or R¹ of A2) is selected from CH₂—OH, —CH(CH₃)—OH— or—CH₂[(C₆H₄)-(4-OH)], or R¹ of the group A3) is selected from —CH₂—NHR″,—(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or C(O)CH₃,R¹ of the group A4) is —CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″wherein R′″ is OR^(5a) wherein R^(5a) is H or a linear (C₁-C₅) alkyl; Tis —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or a straight orbranched C₁-C₄ alkyl; Y is as below defined; or R_(x) is—HN—CH(R^(1a)-T′″-Y′—ONO₂)—COOR^(3a)  (a3) wherein R^(1a) of the groupA5) is selected from CH₂—O—, —CH(CH₃)O— or CH₂[(C₆H₄)O_(p)-], or R^(1a)of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—,—(CH₂)₄—NH—, or R^(1a) of the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—,—(CH₂)₄—C(O)—; R^(3a) is H or a (C₁-C₅) alkyl; T″ is C(O)— or —C(O)—X″wherein X″ is —S— or —O—, when R^(1a) is selected from the group A5) orA6); T″ is —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or astraight or branched C₁-C₄ alkyl, when R^(1a) is selected from the groupA7); Y′ is as below defined; or R_(x) is—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂)  (a5)—R^(1b)—CH(COOR^(3a))NH-(T′-Y—ONO₂)  (a6)—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or  (a9)—R^(1b)—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (a10) wherein R^(1b) of thegroup A8) is selected from —O—CH(CH₃)—, —O—CH₂—, [-4-O)—(C₆H₄)]—CH₂—, orR^(1b) of the group A9) is selected from —HN—CH₂—, —HN—(CH₂)₂—,—HN—(CH₂)₃—, —HN—(CH₂)₄—; R^(3a) is H or a (C₁-C₅) alkyl; R^(4a) is H orC(O)CH₃; T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or astraight or branched C₁-C₄ alkyl; T′ is C(O)— or —C(O)—X″ wherein X″ is—S— or —O—; Y and Y′ are as below defined; or R_(x) is—HN—CH(R^(1a)-T″-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a7) wherein R^(1a) of thegroup A5) is selected from CH₂—O—, —CH(CH₃)—O— or CH₂[(C₆H₄)-(4-O)—], orR^(1a) of the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—,—(CH₂)₃—NH—, —(CH₂)₄—NH—, or R^(1a) of the group A7) is —CH₂—C(O)—,—(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; T″ is C(O)— or —C(O)—X″ wherein X″ is —S—or —O—; T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or astraight or branched C₁-C₄ alkyl, when R^(1a) is selected from A7); T is—O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight orbranched C₁-C₄ alkyl; Y and Y′ are as below defined; or R_(x) is—HN—CH(R²)—CH₂C(O)-(T-Y—ONO₂)  (b1) wherein R² of the group B1) isselected from H, CH₃, isobutyl, isopropyl, benzyl; R² of the group B2)is selected from CH₂—OH, —CH(CH₃)—OH— or CH₂[(C₆H₄)(4-OH)], or R² of thegroup B3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″,—(CH₂)₄—NHR″, wherein R″ is H, or C(O)CH₃, R² of the group B4) is—CH₂—C(O)R′″, —(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is OR^(5a)wherein R^(5a) is H or a linear (C₁-C₅) alkyl; T is —O—, —S—, —NR′—,—O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄ alkyl;Y is as below defined; or R_(x) is selected from—HN—CH(R¹²)—CH₂—O-(T′″-Y—ONO₂)  (d1)—O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)  (d2) wherein R¹² of the group D1) isselected from H, CH₃, isobutyl, isopropyl, benzyl, or R¹² of the groupD2) is selected from CH₂—OH, —CH(CH₃)OH— or CH₂[)C₆H₄)-(4-OH)], or R¹²of the group D3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″,—(CH₂)₄—NHR″ wherein R″ is H, or R¹² of the group D4) is —CH₂—C(O)R′″,—(CH₂)₂—C(O)R′″, —(CH₂)₄—C(O)R′″ wherein R′″ is OR^(5a) wherein R^(5a)is H or a linear (C₁-C₅) alkyl; T′ and T′″ are each independentlyselected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; Y is as belowdefined; or R_(x) is selected from—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂OH  (d3)—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NHR^(4a)  (d4)—HN—CH(R^(12a)-T″-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂) or  (d7)—O—CH₂—CH(R^(12a)-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d8) wherein R^(12a) ofthe group D5) is selected from CH₂—O—, —CH(CH₃)—O— orCH₂[(C₆H₄)-(4-O)—], or R^(12a) of the group D6) is selected from—CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or R^(12a) of the groupD7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—; R^(4a) is H or—C(O)CH₃; T″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or—O—; T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or astraight or branched C₁-C₄ alkyl; T′″ is selected from C(O)— or —C(O)—X″wherein X″ is —S— or —O—; Y and Y′ are as below defined; or R_(x) isselected from—R^(12b)—CH(NHR^(4a))—CH₂—O-(T′″-Y—ONO₂)  (d5)—R^(12b)—CH(CH₂OH)—NH-(T′-Y—ONO₂)  (d6)—R^(12b)—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T′″-Y—ONO₂) or  (d9)—R^(12b)—CH(CH₂—O-T′″-Y′—ONO₂)—NH-(T′-Y—ONO₂)  (d10) wherein R^(12b) ofthe group D8) is selected from —O—CH(CH₃)—, —O—CH₂—,[—O_(p)(C₆H₄)]—CH₂—, or R^(12b) of the group D9) is selected from—HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—; R^(4a) is H or—C(O)—CH₃, T′ and T′″ are each independently selected from —C(O)—,—C(O)—X″, wherein X″ is —S— or —O—; Y and Y′ are each independentlyselected from a) a straight or branched C₁-C₁₀ alkylene, a straight orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or C(O)O—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH—(CH₂)_(n) ^(2′)- and n⁷ is 0, T₁ isC(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein: n² is 1, R¹³ is CH₃; Y¹ is (CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is0; (T₁)′=—O—C(O)—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is alinear or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group; whenY and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH—, n³ is1 or
 2. 4. (canceled)
 5. A compound of formula (I) according to claim 1wherein R, R₁, R₂, R₃, and R₄ are as defined in claim 1; A is 0; R_(x)is—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂) or  (a5)—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9) wherein R^(1b) isC(O)—CH₂—, R^(4a) is H or C(O)CH₃; T is selected from O—, —S—, —NR′—wherein R′ is as above defined, T′ is C(O)— and Y and Y′ are eachindependently selected from a) a straight or branched C₁-C₁₀ alkylene, astraight or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or C(O)O—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH—(CH₂)_(n) ^(2′)- and n⁷ is 0, T₁ isC(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein: n² is 1, R¹³ is CH₃; Y¹ is (CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is0; T₁)′=—O—C(O)—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is alinear or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group; whenY and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH—, n³ is1 or 2;
 6. A compound of formula (I) according to claim 1 wherein R, R₁,R₂, R₃ and R₄ are as defined in claim 1; A is 1 and Z is C(O)—, R_(x) is—R^(1b)—CH(NHR^(4a))—C(O)-(T-Y—ONO₂) or  (a5)—R^(1b)—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)  (a9) wherein R^(1b) of A10)is —O—CH₂— or [—O_(p)—(C₆H₄)]—CH₂—, R^(4a) is H or C(O)CH₃, T isselected from O—, —S—, —NR′— wherein R′ is as above defined, T′ is C(O)—and Y and Y′ are each independently selected from a) a straight orbranched C₁-C₁₀ alkylene, a straight or branched C₁-C₁₀ alkylenesubstituted with a —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or C(O)O—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is —CH═CH—(CH₂)_(n) ^(2′)— and n^(2′) is 0, T₁is C(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein: n² is 1, R¹³ is CH₃; Y¹ is (CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is0; (T₁)′=—O—C(O)—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is alinear or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group; whenY and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′″-Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH—, n³ is1 or
 2. 7. A compound of formula (I) according to claim 1 wherein R, R₁,R₂, R₃ and R₄ are as defined in claim 1; A is 0, R_(x) is—C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)  (b2) wherein R² is H, T′ is C(O)—; Yand Y′ are each independently selected from a) a straight or branchedC₁-C₁₀ alkylene, a straight or branched C₁-C₁₀ alkylene substituted witha —ONO₂ group;

wherein: n² is an integer from 0 to 2, R¹³ is H or CH₃, T₁ is —O—C(O)—or C(O)O—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is a linear orbranched C₁-C₁₀ alkylene substituted with a —ONO₂ group;

n² is 1, R¹³ is CH₃, Y¹ is CH═CH—(CH₂)_(n) ^(2′)- and n⁷ is 0, T₁ isC(O)O— and U is a linear C₁-C₁₀ alkylene;

wherein: n² is 1, R¹³ is CH₃; Y¹ is (CH₂)_(n) ^(2′)—CH═CH— and n^(2′) is0; (T₁)′=—O—C(O)—; n¹ is 1 and U is a linear C₁-C₁₀ alkylene or U is alinear or branched C₁-C₁₀ alkylene substituted with a —ONO₂ group; whenY and Y′ are selected from d), e) or e′), the —ONO₂ group of-(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T′″-Y—ONO₂)and -(T′∝1-Y′—ONO₂) is linked to the (CH₂)— group;—(CH₂—CH₂-T₂)_(n) ₃ —CH₂—CH₂—  f) wherein T₂ is —O— or —S—, —NH— n³ is 1or
 2. 8. (canceled)
 9. (canceled)
 10. A compound of formula (I)according to claim 1 for use in the treatment of ocular diseases. 11.(canceled)
 12. A compound of formula (I) according to claim 1 for use inthe treatment of respiratory diseases.
 13. (canceled)
 14. A compound offormula (I) according to claim 1 for use in the treatment ofdermatological diseases.
 15. (canceled)
 16. (canceled)